46 results on '"Conejo-Garcia J"'
Search Results
2. Tobacco smoking is associated with the immune suppressive microenvironment in head and neck squamous cell carcinoma (HNSCC)
- Author
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Chung, C.H., primary, de la Iglesia, J.V., additional, Wang, X., additional, Song, F., additional, Chaudhary, R., additional, Masannat, J., additional, Conejo-Garcia, J., additional, Hernandez-Prera, J., additional, and Slebos, R., additional
- Published
- 2019
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3. Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors
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Dangaj, D. Bruand, M. Grimm, A.J. Ronet, C. Barras, D. Duttagupta, P.A. Lanitis, E. Duraiswamy, J. Tanyi, J.L. Benencia, F. Conejo-Garcia, J. Ramay, H.R. Montone, K.T. Powell, D.J., Jr. Gimotty, P.A. Facciabene, A. Jackson, D.G. Weber, J.S. Rodig, S.J. Hodi, S.F. Kandalaft, L.E. Irving, M. Zhang, L. Foukas, P. Rusakiewicz, S. Delorenzi, M. Coukos, G.
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stomatognathic diseases ,stomatognathic system ,parasitic diseases ,virus diseases ,hemic and immune systems - Abstract
We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors. Dangaj et al. show that tumor cell-expressed CCL5 and macrophage- and DC-expressed CXCL9 are important for the infiltration of T cells into tumors, a process that also requires recognition of tumor antigens by T cells. CCL5 is often epigenetically silenced in tumor cells but can be reactivated by Decitabine. © 2019 Elsevier Inc.
- Published
- 2019
4. Gonadotropin receptors as targetable biomarkers in advanced, high-grade serous ovarian cancer
- Author
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Mallen, A.R., primary, Han, M., additional, Park, H., additional, Henry, B., additional, Boac, B.M., additional, Wenham, R.M., additional, Conejo-Garcia, J., additional, Xiong, Y., additional, Marchion, D.C., additional, and Magliocco, A., additional
- Published
- 2019
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5. Abstract ES10-3: Blockade of estrogen signaling boosts antitumor immunity by inhibiting tumor-induced pathological myelopoiesis
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Conejo-Garcia, J, primary
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- 2019
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6. Burnout y satisfacción laboral de los profesionales que atienden a pacientes geriátricos
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Bujalance Hoyos, J., Villanueva Pardo, F., Guerrero Manzano, S., Conejo García, J., González Valentín, A., Sepúlveda Jurado, A., Viñas Vera, C., Castro Camacho, S., and Martín Taboada, F.
- Published
- 2001
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7. 1908P - Tobacco smoking is associated with the immune suppressive microenvironment in head and neck squamous cell carcinoma (HNSCC)
- Author
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Chung, C.H., de la Iglesia, J.V., Wang, X., Song, F., Chaudhary, R., Masannat, J., Conejo-Garcia, J., Hernandez-Prera, J., and Slebos, R.
- Published
- 2019
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8. Constitutively activated PI3K accelerates tumor initiation and modifies histopathology of breast cancer
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Sheen, M R, primary, Marotti, J D, additional, Allegrezza, M J, additional, Rutkowski, M, additional, Conejo-Garcia, J R, additional, and Fiering, S, additional
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- 2016
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9. Three-dimensional culture sensitizes epithelial ovarian cancer cells to EZH2 methyltransferase inhibition
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Amatangelo M., Garipov A., Li H., Conejo-Garcia J., Speicher D., and Zhang R.
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3D culture ,endocrine system diseases ,Apoptosis ,macromolecular substances ,EZH2 ,Epithelial ovarian cancer ,EZH2 inhibitor GSK343 - Abstract
Inhibitors of EZH2 methyltransferase activity have been demonstrated to selectively suppress the growth of diffused large B cell lymphoma (DLBCL) cells with gain-of-function mutations in EZH2, while exhibiting very limited effects on the growth of DLBCL cells with wild-type EZH2. Given that EZH2 is often overexpressed but not mutated in solid tumors, it is important to investigate the determinants of sensitivity of solid tumor cells to EZH2 inhibitors. In the current study, we show that three-dimensional (3D) culture of epithelial ovarian cancer (EOC) cells that overexpress EZH2 sensitizes these cells to EZH2 methyltransferase inhibition. Treatment of EOC cells with GSK343, a specific inhibitor of EZH2 methyltransferase, decreases the level of H3K27Me3, the product of EZH2's enzymatic activity. However, GSK343 exhibited limited effects on the growth of EOC cells in conventional two-dimensional (2D) culture. In contrast, GSK343 significantly suppressed the growth of EOC cells cultured in 3D matrigel extracellular matrix (ECM), which more closely mimics the tumor microenvironment in vivo. Notably, GSK343 induces apoptosis of EOC cells in 3D but not 2D culture. In addition, GSK343 significantly inhibited the invasion of EOC cells. In summary, we show that the 3D ECM sensitizes EOC cells to EZH2 methyltransferase inhibition, which suppresses cell growth, induces apoptosis and inhibits invasion. Our findings imply that in EZH2 wild-type solid tumors, the ECM tumor microenvironment plays an important role in determining sensitivity to EZH2 inhibition and suggest that targeting the ECM represents a novel strategy for enhancing EZH2 inhibitor efficacy. © 2013 Landes Bioscience.
- Published
- 2013
10. The role of dendritic cell precursors in tumour vasculogenesis
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Coukos, G, primary, Benencia, F, additional, Buckanovich, R J, additional, and Conejo-Garcia, J R, additional
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- 2005
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11. INTRATUMORAL T-CELLS AND SELECT TUMOR MICROENVIRONMENT SIGNIFICANTLY PREDICT CLINICAL OUTCOME IN ADVANCED OVARIAN CANCER
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Katsaros, D., primary, Zhang, L., additional, Conejo-Garcia, J. R., additional, Fracchioli, S., additional, de la Longrais, I. A. Rigault, additional, Puopolo, M., additional, Kang, E., additional, Massobrio, M., additional, Rubin, S. C., additional, and Coukos, G., additional
- Published
- 2003
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12. NK-1 receptor gene expression is related to pain in chronic pancreatitis.
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Shrikhande, S V, Friess, H, di Mola, F F, Tempia-Caliera, A, Conejo Garcia, J R, Zhu, Z, Zimmermann, A, Büchler, M W, Shrikhande, Shailesh V, Friess, Helmut, di Mola, Fabio F, Tempia-Caliera, Adrien, Conejo Garcia, José R, Zhu, Zhaowen, Zimmermann, Arthur, and Büchler, Markus W
- Published
- 2001
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13. Myristoylated p110α Causes Embryonic Death Due to Developmental and Vascular Defects
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Sheen Mee Rie, Warner Sandra L., Fields Jennifer L., Conejo-Garcia Jose R., and Fiering Steven
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PIK3CA ,p110α ,Cre recombinase ,myristoylated ,lethality ,embryonic development ,morphological malformation ,hemorrhage ,vasculogenesis ,angiogenesis ,Biology (General) ,QH301-705.5 - Abstract
The phosphatidylinositol 3-kinase (PI3K) signaling pathway regulates many important cellular functions. The functional impact of deregulating the PIK3CA gene, encoding the p110α catalytic subunit of PI3K, is validated by frequent gain of function mutations in a range of human cancers. We generated a mouse model with an inducible constitutively active form of PI3K. In this model Cre recombinase activates expression of a myristoylated form of p110α (myr-p110α). The myristoylated version of p110α brings the protein to the cytoplasmic side of the cell membrane, which mimics the normal activation mechanism for the p110α catalytic subunit and activates the PI3K enzyme. Constitutively activated PI3K signaling induced by myr-p110α in all cells of the developing mouse caused lethality during embryonic development. Transgenic Cre;myr-p110α heterozygous embryos displayed morphological malformation and poor vascular development with extremely dilated blood vessels and hemorrhage in the embryo and the extraembryonic yolk sac. Previous studies demonstrated that loss of p110α during embryonic development causes angiogenic disruption and here we show that constitutive activation of p110α by gain of function mutation during development also disrupts vasculogenesis/angiogenesis in what appears to be a similar manner. These finding demonstrate the importance of tight regulation of PI3K signaling during embryonic vasculogenesis/angiogenesis.
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- 2015
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14. Expression of endocrine gland-derived vascular endothelial growth factor in ovarian carcinoma
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Zhang, L., Yang, N., Conejo-Garcia, J. -R, Katsaros, D., Mohamed-Hadley, A., Fracchioli, S., Schlienger, K., Toll, A., Levine, B., Stephen Rubin, and Coukos, G.
15. Identifying alemtuzumab as an anti-myeloid cell antiangiogenic therapy for the treatment of ovarian cancer
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Coukos George, Reynolds R Kevin, Kueck Angela S, McLean Karen, Silva Ines A, Spahlinger Gregory, Pulaski Heather L, Conejo-Garcia Jose R, and Buckanovich Ronald J
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Medicine - Abstract
Abstract Background Murine studies suggest that myeloid cells such as vascular leukocytes (VLC) and Tie2+ monocytes play a critical role in tumor angiogenesis and vasculogenesis. Myeloid cells are a primary cause of resistance to anti-VEGF therapy. The elimination of these cells from the tumor microenvironment significantly restricts tumor growth in both spontaneous and xenograft murine tumor models. Thus animal studies indicate that myeloid cells are potential therapeutic targets for solid tumor therapy. Abundant VLC and Tie2+ monocytes have been reported in human cancer. Unfortunately, the importance of VLC in human cancer growth remains untested as there are no confirmed therapeutics to target human VLC. Methods We used FACS to analyze VLC in ovarian and non-ovarian tumors, and characterize the relationship of VLC and Tie2-monocytes. We performed qRT-PCR and FACS on human VLC to assess the expression of the CD52 antigen, the target of the immunotherapeutic Alemtuzumab. We assessed Alemtuzumab's ability to induce complement-mediated VLC killing in vitro and in human tumor ascites. Finally we assessed the impact of anti-CD52 immuno-toxin therapy on murine ovarian tumor growth. Results Human VLC are present in ovarian and non-ovarian tumors. The majority of VLC appear to be Tie2+ monocytes. VLC and Tie2+ monocytes express high levels of CD52, the target of the immunotherapeutic Alemtuzumab. Alemtuzumab potently induces complement-mediated lysis of VLC in vitro and ex-vivo in ovarian tumor ascites. Anti-CD52 immunotherapy targeting VLC restricts tumor angiogenesis and growth in murine ovarian cancer. Conclusion These studies confirm VLC/myeloid cells as therapeutic targets in ovarian cancer. Our data provide critical pre-clinical evidence supporting the use of Alemtuzumab in clinical trials to test its efficacy as an anti-myeloid cell antiangiogenic therapeutic in ovarian cancer. The identification of an FDA approved anti-VLC agent with a history of clinical use will allow immediate proof-of-principle clinical trials in patients with ovarian cancer.
- Published
- 2009
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16. Cmai: Predicting Antigen-Antibody Interactions from Massive Sequencing Data.
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Song B, Wang K, Na S, Yao J, Fattah FJ, von Itzstein MS, Yang DM, Liu J, Xue Y, Liang C, Guo Y, Raman I, Zhu C, Dowell JE, Homsi J, Rashdan S, Yang S, Gwin ME, Hsiehchen D, Gloria-McCutchen Y, Raj P, Bai X, Wang J, Conejo-Garcia J, Xie Y, Gerber DE, Huang J, and Wang T
- Abstract
The interaction between antigens and antibodies (B cell receptors, BCRs) is the key step underlying the function of the humoral immune system in various biological contexts. The capability to profile the landscape of antigen-binding affinity of a vast number of BCRs will provide a powerful tool to reveal novel insights at unprecedented levels and will yield powerful tools for translational development. However, current experimental approaches for profiling antibody-antigen interactions are costly and time-consuming, and can only achieve low-to-mid throughput. On the other hand, bioinformatics tools in the field of antibody informatics mostly focus on optimization of antibodies given known binding antigens, which is a very different research question and of limited scope. In this work, we developed an innovative Artificial Intelligence tool, Cmai, to address the prediction of the binding between antibodies and antigens that can be scaled to high-throughput sequencing data. Cmai achieved an AUROC of 0.91 in our validation cohort. We devised a biomarker metric based on the output from Cmai applied to high-throughput BCR sequencing data. We found that, during immune-related adverse events (irAEs) caused by immune-checkpoint inhibitor (ICI) treatment, the humoral immunity is preferentially responsive to intracellular antigens from the organs affected by the irAEs. In contrast, extracellular antigens on malignant tumor cells are inducing B cell infiltrations, and the infiltrating B cells have a greater tendency to co-localize with tumor cells expressing these antigens. We further found that the abundance of tumor antigen-targeting antibodies is predictive of ICI treatment response. Overall, Cmai and our biomarker approach filled in a gap that is not addressed by current antibody optimization works nor works such as AlphaFold3 that predict the structures of complexes of proteins that are known to bind.
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- 2024
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17. The T Cell Immunoscore as a Reference for Biomarker Development Utilizing Real-World Data from Patients with Advanced Malignancies Treated with Immune Checkpoint Inhibitors.
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Eljilany I, Saghand PG, Chen J, Ratan A, McCarter M, Carpten J, Colman H, Ikeguchi AP, Puzanov I, Arnold S, Churchman M, Hwu P, Conejo-Garcia J, Dalton WS, Weiner GJ, El Naqa IM, and Tarhini AA
- Abstract
Background: We aimed to determine the prognostic value of an immunoscore reflecting CD3+ and CD8+ T cell density estimated from real-world transcriptomic data of a patient cohort with advanced malignancies treated with immune checkpoint inhibitors (ICIs) in an effort to validate a reference for future machine learning-based biomarker development., Methods: Transcriptomic data was collected under the Total Cancer Care Protocol (NCT03977402) Avatar
® project. The real-world immunoscore for each patient was calculated based on the estimated densities of tumor CD3+ and CD8+ T cells utilizing CIBERSORTx and the LM22 gene signature matrix. Then, the immunoscore association with overall survival (OS) was estimated using Cox regression and analyzed using Kaplan-Meier curves. The OS predictions were assessed using Harrell's concordance index (C-index). The Youden index was used to identify the optimal cut-off point. Statistical significance was assessed using the log-rank test., Results: Our study encompassed 522 patients with four cancer types. The median duration to death was 10.5 months for the 275 participants who encountered an event. For the entire cohort, the results demonstrated that transcriptomics-based immunoscore could significantly predict patients at risk of death ( p -value < 0.001). Notably, patients with an intermediate-high immunoscore achieved better OS than those with a low immunoscore. In subgroup analysis, the prediction of OS was significant for melanoma and head and neck cancer patients but did not reach significance in the non-small cell lung cancer or renal cell carcinoma cohorts., Conclusions: Calculating CD3+ and CD8+ T cell immunoscore using real-world transcriptomic data represents a promising signature for estimating OS with ICIs and can be used as a reference for future machine learning-based biomarker development.- Published
- 2023
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18. Associations between prediagnostic aspirin use and ovarian tumor gene expression.
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Sasamoto N, Stewart PA, Wang T, Thompson ZJ, Yoder SJ, Hecht JL, Cleveland JL, Conejo-Garcia J, Fridley BL, Terry KL, and Tworoger SS
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- Female, Humans, Case-Control Studies, Gene Expression, Estrogens, Aspirin adverse effects, Ovarian Neoplasms pathology
- Abstract
Background: Aspirin use has been associated with reduced ovarian cancer risk, yet the underlying biological mechanisms are not fully understood. To gain mechanistic insights, we assessed the association between prediagnosis low and regular-dose aspirin use and gene expression profiles in ovarian tumors., Methods: RNA sequencing was performed on high-grade serous, poorly differentiated, and high-grade endometrioid ovarian cancer tumors from the Nurses' Health Study (NHS), NHSII, and New England Case-Control Study (n = 92 cases for low, 153 cases for regular-dose aspirin). Linear regression identified differentially expressed genes associated with aspirin use, adjusted for birth decade and cohort. False discovery rates (FDR) were used to account for multiple testing and gene set enrichment analysis was used to identify biological pathways., Results: No individual genes were significantly differentially expressed in ovarian tumors in low or regular-dose aspirin users accounting for multiple comparisons. However, current versus never use of low-dose aspirin was associated with upregulation of immune pathways (e.g., allograft rejection, FDR = 5.8 × 10
-10 ; interferon-gamma response, FDR = 2.0 × 10-4 ) and downregulation of estrogen response pathways (e.g., estrogen response late, FDR = 4.9 × 10-8 ). Ovarian tumors from current regular aspirin users versus never users were also associated with upregulation in interferon pathways (FDR <1.5 × 10-4 ) and downregulation of multiple extracellular matrix (ECM) architecture pathways (e.g., ECM organization, 4.7 × 10-8 )., Conclusion: Our results suggest low and regular-dose aspirin may impair ovarian tumorigenesis in part via enhancing adaptive immune response and decreasing metastatic potential supporting the likely differential effects on ovarian carcinogenesis and progression by dose of aspirin., (© 2023 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.)- Published
- 2023
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19. Enhanced immune activation within the tumor microenvironment and circulation of female high-risk melanoma patients and improved survival with adjuvant CTLA4 blockade compared to males.
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Saad M, Lee SJ, Tan AC, El Naqa IM, Hodi FS, Butterfield LH, LaFramboise WA, Storkus W, Karunamurthy AD, Conejo-Garcia J, Hwu P, Streicher H, Sondak VK, Kirkwood JM, and Tarhini AA
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- Adjuvants, Immunologic therapeutic use, CTLA-4 Antigen genetics, Female, Humans, Interferon-alpha, Ipilimumab therapeutic use, Leukocytes, Mononuclear pathology, Male, Neoplasm Recurrence, Local pathology, Neoplasm Staging, Tumor Microenvironment, Melanoma drug therapy, Melanoma genetics, Skin Neoplasms drug therapy, Skin Neoplasms genetics
- Abstract
Background: We hypothesized that a gender difference in clinical response may exist to adjuvant CTLA4 blockade with ipilimumab versus high-dose IFNα (HDI). We investigated differences in candidate immune biomarkers in the circulation and tumor microenvironment (TME)., Patients and Methods: This gender-based analysis was nested within the E1609 trial that tested adjuvant therapy with ipilimumab 3 mg/kg (ipi3) and 10 mg/kg (ipi10) versus HDI in high risk resected melanoma. We investigated gender differences in treatment efficacy with ipi3 and ipi10 versus HDI while adjusting for age, stage, ECOG performance (PS), ulceration, primary tumor status and lymph node number. Forest plots were created to compare overall survival (OS) and relapse free survival (RFS) between ipi and HDI. Gene expression profiling (GEP) was performed on tumors of 718 (454 male, 264 female) patients. Similarly, serum and peripheral blood mononuclear cells (PBMC) samples were tested for soluble and cellular biomarkers (N = 321 patients; 109 female and 212 male)., Results: The subgroups of female, stage IIIC, PS = 1, ulcerated primary, in-transit metastasis demonstrated significant improvement in RFS and/or OS with ipi3 versus HDI. Female gender was significant for both OS and RFS and was further explored. In the RFS comparison, a multivariate Cox regression model including significant variables indicated a significant interaction between gender and treatment (P = 0.024). In peripheral blood, percentages of CD3+ T cells (P = 0.024) and CD3+ CD4+ helper T cells (P = 0.0001) were higher in females compared to males. Trends toward higher circulating levels of IL1β (P = 0.07) and IL6 (P = 0.06) were also found in females. Males had higher percentages of monocytes (P = 0.03) with trends toward higher percentages of regulatory T cells (T-reg). Tumor GEP analysis supported enhanced infiltration with immune cells including gammadelta T cells (P = 0.005), NK cells (P = 0.01), dendritic cells (P = 0.01), CD4+ T cells (P = 0.03), CD8+ T cells (P = 0.03) and T-reg (P = 0.008) in the tumors of females compared to males and a higher T-effector and IFNγ gene signature score (P = 0.0244)., Conclusion: Female gender was associated with adjuvant CTLA4 blockade clinical benefits and female patients were more likely to have evidence of type1 immune activation within the TME and the circulation. Trial registration ClinicalTrials.gov NCT01274338. Registered 11 January 2011, https://www., Clinicaltrials: gov/ct2/show/NCT01274338., (© 2022. The Author(s).)
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- 2022
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20. Pharmacologic Tumor PDL1 Depletion with Cefepime or Ceftazidime Promotes DNA Damage and Sensitivity to DNA-Damaging Agents.
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Murray C, Galvan E, Ontiveros C, Deng Y, Bai H, Padron AS, Hinchee-Rodriguez K, Garcia MG, Kornepati A, Conejo-Garcia J, and Curiel TJ
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- Animals, Cefepime pharmacology, Ceftazidime, DNA Damage, Mice, B7-H1 Antigen metabolism, Melanoma
- Abstract
The interaction between tumor surface-expressed PDL1 and immune cell PD1 for the evasion of antitumor immunity is well established and is targeted by FDA-approved anti-PDL1 and anti-PD1 antibodies. Nonetheless, recent studies highlight the immunopathogenicity of tumor-intrinsic PDL1 signals that can contribute to the resistance to targeted small molecules, cytotoxic chemotherapy, and αPD1 immunotherapy. As genetic PDL1 depletion is not currently clinically tractable, we screened FDA-approved drugs to identify those that significantly deplete tumor PDL1. Among the candidates, we identified the β-lactam cephalosporin antibiotic cefepime as a tumor PDL1-depleting drug (PDD) that increases tumor DNA damage and sensitivity to DNA-damaging agents in vitro in distinct aggressive mouse and human cancer lines, including glioblastoma multiforme, ovarian cancer, bladder cancer, and melanoma. Cefepime reduced tumor PDL1 post-translationally through ubiquitination, improved DNA-damaging-agent treatment efficacy in vivo in immune-deficient and -proficient mice, activated immunogenic tumor STING signals, and phenocopied specific genetic PDL1 depletion effects. The β-lactam ring and its antibiotic properties did not appear contributory to PDL1 depletion or to these treatment effects, and the related cephalosporin ceftazidime produced similar effects. Our findings highlight the rapidly translated potential for PDDs to inhibit tumor-intrinsic PDL1 signals and improve DNA-damaging agents and immunotherapy efficacy.
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- 2022
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21. Clinical characteristics and prognostic factors of 70 patients with Sézary syndrome: a single-institutional experience at Moffitt cancer center.
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Zhang Y, Seminario-Vidal L, Varnadoe C, Lu Y, Dong N, Salamanca C, Whiddon S, Bennett J, Hargis R, Liu H, Montejo M, Hussaini M, Harro C, Messina J, Benson K, Pinilla-Ibarz J, Conejo-Garcia J, and Sokol L
- Subjects
- Humans, Male, Prognosis, Retrospective Studies, Lymphoma, T-Cell, Cutaneous pathology, Mycosis Fungoides pathology, Sezary Syndrome diagnosis, Sezary Syndrome pathology, Sezary Syndrome therapy, Skin Neoplasms diagnosis, Skin Neoplasms therapy
- Abstract
Sézary syndrome (SS) is a rare and aggressive leukemic variant of cutaneous T-cell lymphoma, with a median overall survival (OS) rate of 2-4 years. Few studies have described the clinical outcome of SS patients since 2012. We retrospectively analyzed 70 patients diagnosed with SS treated at a high-volume tertiary cancer center between 2000 and 2018. Overall survival at 1 and 5 years was 84.1% and 50.7%, respectively. Univariate analyses identified older age (>65 years) and male sex as poor prognostic factors. Five patients presented with circulating large granular lymphocytic proliferation and had a favorable prognosis. Targeted therapies were effective in treating refractory/relapsed SS patients with a durable response. Therapeutic advancements and the comprehensive treatments used in a multidisciplinary clinic improved OS rates.
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- 2022
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22. Correction: Effects of Tobacco Smoking On the Tumor Immune Microenvironment in Head and Neck Squamous Cell Carcinoma.
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de la Iglesia JV, Slebos RJC, Martin-Gomez L, Wang X, Teer JK, Tan AC, Gerke TA, Aden-Buie G, van Veen T, Masannat J, Chaudhary R, Song F, Fournier M, Siegel EM, Schabath MB, Wadsworth JT, Caudell J, Harrison L, Wenig BM, Conejo-Garcia J, Hernandez-Prera JC, and Chung CH
- Published
- 2021
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23. Using oncolytic viruses to ignite the tumour immune microenvironment in bladder cancer.
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Li R, Zhang J, Gilbert SM, Conejo-Garcia J, and Mulé JJ
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- Adaptive Immunity immunology, Alarmins immunology, Antigens, Neoplasm immunology, Carcinoma, Transitional Cell immunology, Combined Modality Therapy, Cytokines immunology, Humans, Immunity, Innate immunology, Inflammation immunology, Oncolytic Viruses, Urinary Bladder Neoplasms immunology, Carcinoma, Transitional Cell therapy, Immune Checkpoint Inhibitors therapeutic use, Oncolytic Virotherapy, Tumor Microenvironment immunology, Urinary Bladder Neoplasms therapy
- Abstract
The advent of immune checkpoint inhibition (ICI) has transformed the treatment paradigm for bladder cancer. However, despite the success of ICI in other tumour types, the majority of ICI-treated patients with bladder cancer failed to respond. The lack of efficacy in some patients could be attributed to a paucity of pre-existing immune reactive cells within the tumour immune microenvironment, which limits the beneficial effects of ICI. In this setting, strategies to attract lymphocytes before implementation of ICI could be helpful. Oncolytic virotherapy is thought to induce the release of damage-associated molecular patterns, eliciting a pro-inflammatory cytokine cascade and stimulating the activation of the innate immune system. Concurrently, oncolytic virotherapy-induced oncolysis leads to further release of neoantigens and subsequent epitope spreading, culminating in a robust, tumour-specific adaptive immune response. Combination therapy using oncolytic virotherapy with ICI has proven successful in a number of preclinical studies and is beginning to enter clinical trials for the treatment of both non-muscle-invasive and muscle-invasive bladder cancer. In this context, understanding of the mechanisms underpinning oncolytic virotherapy and its potential synergism with ICI will enable clinicians to effectively deploy oncolytic virotherapy, either as monotherapy or as combination therapy in the different clinical stages of bladder cancer., (© 2021. Springer Nature Limited.)
- Published
- 2021
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24. The Cancer Epitope Database and Analysis Resource: A Blueprint for the Establishment of a New Bioinformatics Resource for Use by the Cancer Immunology Community.
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Koşaloğlu-Yalçın Z, Blazeska N, Carter H, Nielsen M, Cohen E, Kufe D, Conejo-Garcia J, Robbins P, Schoenberger SP, Peters B, and Sette A
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- Antigens, Neoplasm genetics, Databases, Genetic, Humans, Immunotherapy, Mutation, Neoplasms genetics, Neoplasms therapy, Receptors, Antigen, B-Cell genetics, Receptors, Antigen, B-Cell immunology, Receptors, Antigen, T-Cell genetics, Receptors, Antigen, T-Cell immunology, Tumor Microenvironment, Antigens, Neoplasm immunology, Computational Biology, Epitopes, B-Lymphocyte, Epitopes, T-Lymphocyte, Neoplasms immunology
- Abstract
Recent years have witnessed a dramatic rise in interest towards cancer epitopes in general and particularly neoepitopes, antigens that are encoded by somatic mutations that arise as a consequence of tumorigenesis. There is also an interest in the specific T cell and B cell receptors recognizing these epitopes, as they have therapeutic applications. They can also aid in basic studies to infer the specificity of T cells or B cells characterized in bulk and single-cell sequencing data. The resurgence of interest in T cell and B cell epitopes emphasizes the need to catalog all cancer epitope-related data linked to the biological, immunological, and clinical contexts, and most importantly, making this information freely available to the scientific community in a user-friendly format. In parallel, there is also a need to develop resources for epitope prediction and analysis tools that provide researchers access to predictive strategies and provide objective evaluations of their performance. For example, such tools should enable researchers to identify epitopes that can be effectively used for immunotherapy or in defining biomarkers to predict the outcome of checkpoint blockade therapies. We present here a detailed vision, blueprint, and work plan for the development of a new resource, the C ancer E pitope D atabase and A nalysis R esource (CEDAR). CEDAR will provide a freely accessible, comprehensive collection of cancer epitope and receptor data curated from the literature and provide easily accessible epitope and T cell/B cell target prediction and analysis tools. The curated cancer epitope data will provide a transparent benchmark dataset that can be used to assess how well prediction tools perform and to develop new prediction tools relevant to the cancer research community., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Koşaloğlu-Yalçın, Blazeska, Carter, Nielsen, Cohen, Kufe, Conejo-Garcia, Robbins, Schoenberger, Peters and Sette.)
- Published
- 2021
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25. The 12-CK Score: Global Measurement of Tertiary Lymphoid Structures.
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Li R, Berglund A, Zemp L, Dhillon J, Putney R, Kim Y, Jain RK, Grass GD, Conejo-Garcia J, and Mulé JJ
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- Clinical Decision-Making, Female, Humans, Immunotherapy, Male, Neoplasms immunology, Neoplasms therapy, Predictive Value of Tests, Prognosis, Tumor Microenvironment, Biomarkers, Tumor genetics, Chemokines genetics, Gene Expression Profiling, Neoplasms genetics, Tertiary Lymphoid Structures immunology, Transcriptome
- Abstract
There is emerging evidence that the adaptive anti-tumor activity may be orchestrated by secondary lymphoid organ-like aggregates residing in the tumor microenvironment. Known as tertiary lymphoid structures, these lymphoid aggregates serve as key outposts for lymphocyte recruitment, priming and activation. They have been linked to favorable outcomes in many tumor types, and more recently, have been shown to be effective predictors of response to immune checkpoint blockade. We have previously described a 12-chemokine (12-CK) transcriptional score which recapitulates an overwhelming enrichment for immune-related and inflammation-related genes in colorectal carcinoma. Subsequently, the 12-CK score was found to prognosticate favorable survival in multiple tumors types including melanoma, breast cancer, and bladder cancer. In the current study, we summarize the discovery and validation of the 12-CK score in various tumor types, its relationship to TLSs found within the tumor microenvironment, and explore its potential role as both a prognostic and predictive marker in the treatment of various cancers., Competing Interests: RL: Clinical trial protocol committee - Cold Genesys, BMS; Scientific advisor/consultant – BMS, Fergene. JM: Associate Center Director at Moffitt Cancer Center, has ownership interest in Fulgent Genetics, Inc., Aleta Biotherapeutics, Inc., CG Oncology, Inc., Myst Pharma, Inc., Verseau Therapeutics, Inc., AffyImmune, Inc., and Tailored Therapeutics, Inc., and is a paid consultant/paid advisory board member for ONCoPEP, Inc., CG Oncology, Inc., Morphogenesis, Inc., Mersana Therapeutics, Inc., GammaDelta Therapeutics, Ltd., Myst Pharma, Inc., Tailored Therapeutics, Inc., Verseau Therapeutics, Inc., Iovance Biotherapeutics, Vault Pharma, Inc., Noble Life Sciences, and Fulgent Genetics, Inc., UbiVac, LLC, Vycellix, Inc., AffyImmune, Inc., and Aleta Biotherapeutics, Inc. A patent on the 12 chemokine gene expression signature in bladder cancer was issued on March 10, 2020, titled, “Immune Gene Signatures in Urothelial Carcinoma (UC)” (10,583,183). Inventors are: JM, Anthony M. Magliocco, and AB. A provisional patent application was filed on August 27, 2020, titled “Immune Gene Signature in Muscle Invasive Bladder Cancer” (Serial No. 63/071,320). Inventors are: RL, JM, and AB. The remaining authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Li, Berglund, Zemp, Dhillon, Putney, Kim, Jain, Grass, Conejo-Garcia and Mulé.)
- Published
- 2021
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26. Targeting Ovarian Cancer with IL-2 Cytokine/Antibody Complexes: A Summary and Recent Advances.
- Author
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Deng Y, Reyes RM, Zhang C, Conejo-Garcia J, and Curiel TJ
- Abstract
Competing Interests: Conflict of Interest Statement All authors declared no conflict of interest.
- Published
- 2021
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27. Cancer Moonshot Immuno-Oncology Translational Network (IOTN): accelerating the clinical translation of basic discoveries for improving immunotherapy and immunoprevention of cancer.
- Author
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Annapragada A, Sikora A, Bollard C, Conejo-Garcia J, Cruz CR, Demehri S, Demetriou M, Demirdjian L, Fong L, Horowitz M, Hutson A, Kadash-Edmondson K, Kufe D, Lipkin S, Liu S, McCarthy C, Morgan M, Morris Z, Pan Y, Pasquini M, Schoenberger S, Van Allen E, Vilar E, Xing Y, Zha W, and Odunsi A
- Subjects
- Humans, Immunotherapy methods, Medical Oncology organization & administration, Neoplasms drug therapy, Neoplasms immunology
- Abstract
Despite regulatory approval of several immune-based treatments for cancer in the past decade, a number of barriers remain to be addressed in order to fully harness the therapeutic potential of the immune system and provide benefits for patients with cancer. As part of the Cancer Moonshot initiative, the Immuno-Oncology Translational Network (IOTN) was established to accelerate the translation of basic discoveries to improve immunotherapy outcomes across the spectrum of adult cancers and to develop immune-based approaches that prevent cancers before they occur. The IOTN currently consists of 32 academic institutions in the USA. By leveraging cutting-edge preclinical research in immunotherapy and immunoprevention, open data and resource sharing, and fostering highly collaborative team science across the immuno-oncology ecosystem, the IOTN is designed to accelerate the generation of novel mechanism-driven immune-based cancer prevention and therapies, and the development of safe and effective personalized immuno-oncology approaches., Competing Interests: Competing interests: AA is a board member and receives research grant from Alzeca. He is also a stockholder of Alzeca, Sensulin LLC., and Abbott Laboratories. AS receives grant funds from Tessa Therapeutics and Heat/Pelican Therapeutics, and serves on the data safety monitoring board of a Phase III clinical trial by Tessa Therapeutics. CB serves consulting or advisory role to Cellectis and Mana Therapeutics, and holds stock options or other ownership of Mana Therapeutics, Torque, Neximmune, and Cabaletta Bio. JC-G receives research supports, holds stock options and severs as member of the ethics advisory board to Compass Therapeutics and Anixa Biosciences. CRC is a cofounder of Mana Therapeutics, a biotechnology company developing T cell-based therapies for cancer. MD is an inventor on a patent that describes glycan-targeting bispecific proteins and CAR cells for cancer immunotherapy, and is a cofounder of GlyTR Therapeutics. LF receives research support from Abbvie, Bavarian Nordic, BMS, Dendreon, Janssen, Merck, and Roche/Genentech. DK has equity interests in Genus Oncology, Reata Pharmaceuticals, Hillstream BioPharma, Nanogen Therapeutics, and Victa BioTherapeutics. He also serves as a member of the board of directors of Nanogen and Victa, and is a paid consultant to Reata, CanBas and Victa. ZM receives research agreements/material support from BMS, AstraZeneca, Archeus Technologies, and Seneca Therapeutics, and is on the scientific advisory board to Archeus Technologies and Seneca Therapeutics. He also has patents filed in in situ Immune Modulated Cancer Vaccination, using targeted radiotherapy and bacterial membrane nanoparticles in immunotherapies, and multipurpose catheter for brachytherapy and intratumoral injection. EVA holds an advisory/consulting role to Tango Therapeutics, Genome Medical, Invitae, Illumina, and is an equity holder of Tango Therapeutics, Genome Medical, Syapse, Ervaxx, and Microsoft. He receives research support from Novartis and BMS, and travel reimbursement from Roche/Genentech. He also has institutional patents filed on ERCC2 mutations and chemotherapy response, chromatin mutations and immunotherapy response, and methods for clinical interpretation. EV has a consulting or advisory role with Janssen Research and Development and TFS Oncology. AO is a cofounder of Tactiva Therapeutics, a biotechnology company developing T cell-based therapies for cancer, receives research support from Astra Zeneca and Tessaro. YX is a scientific cofounder of Panorama Medicine., (© Author(s) (or their employer(s)) 2020. Re-use permitted under CC BY. Published by BMJ.)
- Published
- 2020
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28. Effects of Tobacco Smoking on the Tumor Immune Microenvironment in Head and Neck Squamous Cell Carcinoma.
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de la Iglesia JV, Slebos RJC, Martin-Gomez L, Wang X, Teer JK, Tan AC, Gerke TA, Aden-Buie G, van Veen T, Masannat J, Chaudhary R, Song F, Fournier M, Siegel EM, Schabath MB, Wadsworth JT, Caudell J, Harrison L, Wenig BM, Conejo-Garcia J, Hernandez-Prera JC, and Chung CH
- Subjects
- Adult, Aged, Aged, 80 and over, Biomarkers, Tumor immunology, Biomarkers, Tumor metabolism, Chemokine CXCL10 metabolism, Chemokine CXCL11 metabolism, Chemokine CXCL9 metabolism, Female, Head and Neck Neoplasms metabolism, Head and Neck Neoplasms pathology, Humans, Lymphocytes, Tumor-Infiltrating drug effects, Male, Middle Aged, Retrospective Studies, Squamous Cell Carcinoma of Head and Neck metabolism, Squamous Cell Carcinoma of Head and Neck pathology, Tumor Microenvironment drug effects, Young Adult, Head and Neck Neoplasms immunology, Interferon-alpha immunology, Interferon-gamma immunology, Lymphocytes, Tumor-Infiltrating immunology, Squamous Cell Carcinoma of Head and Neck immunology, Tobacco Smoking adverse effects, Tumor Microenvironment immunology
- Abstract
Purpose: Patients with head and neck squamous cell carcinoma (HNSCC) who actively smoke during treatment have worse survival compared with never-smokers and former-smokers. We hypothesize the poor prognosis in tobacco smokers with HNSCC is, at least in part, due to ongoing suppression of immune response. We characterized the tumor immune microenvironment (TIM) of HNSCC in a retrospective cohort of 177 current, former, and never smokers., Experimental Design: Tumor specimens were subjected to analysis of CD3, CD8, FOXP3, PD-1, PD-L1, and pancytokeratin by multiplex immunofluorescence, whole-exome sequencing, and RNA sequencing. Immune markers were measured in tumor core, tumor margin, and stroma., Results: Our data indicate that current smokers have significantly lower numbers of CD8
+ cytotoxic T cells and PD-L1+ cells in the TIM compared with never- and former-smokers. While tumor mutation burden and mutant allele tumor heterogeneity score do not associate with smoking status, gene-set enrichment analyses reveal significant suppression of IFNα and IFNγ response pathways in current smokers. Gene expression of canonical IFN response chemokines, CXCL9 , CXCL10 , and CXCL11 , are lower in current smokers than in former smokers, suggesting a mechanism for the decreased immune cell migration to tumor sites., Conclusions: These results suggest active tobacco use in HNSCC has an immunosuppressive effect through inhibition of tumor infiltration of cytotoxic T cells, likely as a result of suppression of IFN response pathways. Our study highlights the importance of understanding the interaction between smoking and TIM in light of emerging immune modulators for cancer management., (©2019 American Association for Cancer Research.)- Published
- 2020
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29. Cooperation between Constitutive and Inducible Chemokines Enables T Cell Engraftment and Immune Attack in Solid Tumors.
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Dangaj D, Bruand M, Grimm AJ, Ronet C, Barras D, Duttagupta PA, Lanitis E, Duraiswamy J, Tanyi JL, Benencia F, Conejo-Garcia J, Ramay HR, Montone KT, Powell DJ Jr, Gimotty PA, Facciabene A, Jackson DG, Weber JS, Rodig SJ, Hodi SF, Kandalaft LE, Irving M, Zhang L, Foukas P, Rusakiewicz S, Delorenzi M, and Coukos G
- Subjects
- Animals, Antineoplastic Agents, Immunological pharmacology, CD8-Positive T-Lymphocytes drug effects, CD8-Positive T-Lymphocytes immunology, Cell Line, Tumor, Chemokine CCL5 genetics, Chemokine CCL5 immunology, Chemokine CCL5 metabolism, Chemokine CXCL9 genetics, Chemokine CXCL9 immunology, Chemokine CXCL9 metabolism, Coculture Techniques, Cytokines genetics, Cytokines immunology, DNA Methylation, Dendritic Cells drug effects, Dendritic Cells immunology, Epigenesis, Genetic, Female, Gene Expression Regulation, Neoplastic, Humans, Immunotherapy methods, Interferon-gamma genetics, Interferon-gamma immunology, Interferon-gamma metabolism, Lymphocytes, Tumor-Infiltrating drug effects, Lymphocytes, Tumor-Infiltrating immunology, Macrophages drug effects, Macrophages immunology, Mice, Inbred C57BL, Ovarian Neoplasms immunology, Ovarian Neoplasms pathology, Ovarian Neoplasms therapy, Paracrine Communication, Receptors, CXCR3 genetics, Receptors, CXCR3 immunology, Receptors, CXCR3 metabolism, Signal Transduction, CD8-Positive T-Lymphocytes metabolism, Chemotaxis, Leukocyte drug effects, Cytokines metabolism, Dendritic Cells metabolism, Lymphocyte Activation drug effects, Lymphocytes, Tumor-Infiltrating metabolism, Macrophages metabolism, Ovarian Neoplasms metabolism
- Abstract
We investigated the role of chemokines in regulating T cell accumulation in solid tumors. CCL5 and CXCL9 overexpression was associated with CD8
+ T cell infiltration in solid tumors. T cell infiltration required tumor cell-derived CCL5 and was amplified by IFN-γ-inducible, myeloid cell-secreted CXCL9. CCL5 and CXCL9 coexpression revealed immunoreactive tumors with prolonged survival and response to checkpoint blockade. Loss of CCL5 expression in human tumors was associated with epigenetic silencing through DNA methylation. Reduction of CCL5 expression caused tumor-infiltrating lymphocyte (TIL) desertification, whereas forced CCL5 expression prevented Cxcl9 expression and TILs loss, and attenuated tumor growth in mice through IFN-γ. The cooperation between tumor-derived CCL5 and IFN-γ-inducible CXCR3 ligands secreted by myeloid cells is key for orchestrating T cell infiltration in immunoreactive and immunoresponsive tumors., (Copyright © 2019 Elsevier Inc. All rights reserved.)- Published
- 2019
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30. Effect of cyclical intermittent hypoxia on Ad5CMVCre induced solitary lung cancer progression and spontaneous metastases in the KrasG12D+; p53fl/fl; myristolated p110fl/fl ROSA-gfp mouse.
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Guo X, Liu Y, Kim JL, Kim EY, Kim EQ, Jansen A, Li K, Chan M, Keenan BT, Conejo-Garcia J, and Lim DC
- Subjects
- Animals, Cytomegalovirus genetics, Disease Progression, Humans, Hypoxia genetics, Male, Mediastinum pathology, Mice, Mice, Transgenic, Myocardium pathology, Neoplasm Metastasis diagnostic imaging, Neoplasm Metastasis pathology, Ribs pathology, Solitary Pulmonary Nodule diagnostic imaging, Solitary Pulmonary Nodule genetics, X-Ray Microtomography, Class I Phosphatidylinositol 3-Kinases genetics, Cytomegalovirus physiology, Hypoxia complications, Proto-Oncogene Proteins p21(ras) genetics, Solitary Pulmonary Nodule pathology, Tumor Suppressor Protein p53 genetics
- Abstract
Background: Epidemiological data suggests that obstructive sleep apnea (OSA) is associated with increased cancer incidence and mortality. We investigate the effects of cyclical intermittent hypoxia (CIH), akin to the underlying pathophysiology of OSA, on lung cancer progression and metastatic profile in a mouse model., Methods: Intrathoracic injection of Ad5CMVCre virus into a genetically engineered mouse (GEM) KrasG12D+/-; p53fl/fl; myristolated-p110αfl/fl-ROSA-gfp was utilized to induce a solitary lung cancer. Male mice were then exposed to either CIH or Sham for 40-41 days until harvest. To monitor malignant progression, serial micro CT scans with respiratory gating (no contrast) was performed. To detect spontaneous metastases in distant organs, H&E and immunohistochemistry were performed., Results: Eighty-eight percent of injected Ad5CMVCre virus was recovered from left lung tissue, indicating reliable and accurate injections. Serial micro CT demonstrated that CIH increases primary lung tumor volume progression compared to Sham on days 33 (p = 0.004) and 40 (p<0.001) post-injection. In addition, CIH increases variability in tumor volume on day 19 (p<0.0001), day 26 (p<0.0001), day 33 (p = 0.025) and day 40 (p = 0.004). Finally, metastases are frequently detected in heart, mediastinal lymph nodes, and right lung using H&E and immunohistochemistry., Conclusions: Using a GEM mouse model of metastatic lung cancer, we report that male mice with solitary lung cancer have accelerated malignant progression and increased variability in tumor growth when exposed to cyclical intermittent hypoxia. Our results indicate that cyclical intermittent hypoxia is a pathogenic factor in non-small cell lung cancer that promotes the more rapid growth of developing tumors., Competing Interests: This is not an industry-supported study. JCG: External Advisory Boards: KSQ Therapeutics, ITUS, Compass Therapeutics; Sponsored research: Compass Therapeutics, ITUS. This does not alter our adherence to PLOS ONE policies on sharing data and materials.
- Published
- 2019
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31. PD-1/PD-L1 immune checkpoint inhibitors in advanced cervical cancer.
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Saglam O and Conejo-Garcia J
- Abstract
Programmed cell death-1 and programmed cell death ligand-1 (PD-1/PD-L1) blockage has become an important treatment modality after approval of pembrolizumab and nivolumab by Food and Drug Administration in advanced cancers. Patients with metastatic and recurrent cervical cancer have limited treatment options and usually receive palliative platinum-based chemotherapy without significant survival benefit. Recent studies provided support for usage of immune checkpoint inhibitors in advanced cervical cancer. Around 35% of cervical squamous cell carcinoma (C-SCC) and 17% of adenocarcinomas expressed PD-L1. Human Papilloma Virus status was also correlated with PD-L1 expression. PD-1/PD-L1 expression in tumor infiltrating inflammatory cells was higher in cervical cancer in comparison to endometrial and ovarian adenocarcinomas. In C-SCC diffuse PD-L1 expression as compared to marginal PD-L1 expression on the interface between tumor and stroma was a risk factor for poor disease-free and disease-specific survival rates. Higher numbers of infiltrating regulatory T cells in PD-L1 positive tumors was associated with better prognosis. The studies performed on other cancer types revealed PD-L1 tumor heterogeneity and transient marker expression. Drug-resistance to immune checkpoint inhibitors is also a potential problem. Currently Phase I/II clinical trials evaluating effects of PD-1 therapy are in progress for cervical carcinoma. Additional studies are required to develop novel biomarkers and for standard evaluation of PD-L1 testing in order to predict response to immune checkpoint inhibitors in all cancer types including cervical carcinoma.
- Published
- 2018
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32. Immunotherapy for Breast Cancer: Current and Future Strategies.
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Williams AD, Payne KK, Posey AD Jr, Hill C, Conejo-Garcia J, June CH, and Tchou J
- Abstract
Purpose of Review: The breast tumor microenvironment is immunosuppressive and is increasingly recognized to play a significant role in tumorigenesis. A deeper understanding of normal and aberrant interactions between malignant and immune cells has allowed researchers to harness the immune system with novel immunotherapy strategies, many of which have shown promise in breast cancer. This review discusses the application of immunotherapy to the treatment of breast cancer., Recent Findings: Both basic science and clinical trial data are rapidly developing in the use of immunotherapy for breast cancer. The current clinical trial landscape includes therapeutic vaccines, immune checkpoint blockade, antibodies, cytokines, and adoptive cell therapy., Summary: Despite early failures, the application of immunotherapeutic strategies to the treatment of breast cancer holds promise., Competing Interests: Conflict of interest Dr. June reports grants from Novartis, outside the submitted work; In addition, Dr. June has a patent 9464140, 9161971, 8975071, 8916381, and 8906682, with royalties paid to Novartis. Carl June is a scientific founder of Tmunity Therapeutics, a biotech dedicated to developing engineered T cells for therapy of cancer, infections and autoimmunity. Dr. June has founders stock from Tmunity. Ms. Hill, Drs. Williams, Posey, Conejo-Garcia, Tchou, and Payne declare no conflicts of interest relevant to this manuscript.
- Published
- 2017
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33. Tumor-Intrinsic PD-L1 Signals Regulate Cell Growth, Pathogenesis, and Autophagy in Ovarian Cancer and Melanoma.
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Clark CA, Gupta HB, Sareddy G, Pandeswara S, Lao S, Yuan B, Drerup JM, Padron A, Conejo-Garcia J, Murthy K, Liu Y, Turk MJ, Thedieck K, Hurez V, Li R, Vadlamudi R, and Curiel TJ
- Subjects
- Animals, Autophagy, B7-H1 Antigen metabolism, Cell Line, Tumor, Cell Proliferation, Female, Humans, Mice, Mice, Knockout, Ovarian Neoplasms pathology, Signal Transduction, Transfection, B7-H1 Antigen genetics, Melanoma genetics, Ovarian Neoplasms genetics
- Abstract
PD-L1 antibodies produce efficacious clinical responses in diverse human cancers, but the basis for their effects remains unclear, leaving a gap in the understanding of how to rationally leverage therapeutic activity. PD-L1 is widely expressed in tumor cells, but its contributions to tumor pathogenicity are incompletely understood. In this study, we evaluated the hypothesis that PD-L1 exerts tumor cell-intrinsic signals that are critical for pathogenesis. Using RNAi methodology, we attenuated PD-L1 in the murine ovarian cell line ID8agg and the melanoma cell line B16 (termed PD-L1
lo cells), which express basal PD-L1. We observed that PD-L1lo cells proliferated more weakly than control cells in vitro As expected, PD-L1lo cells formed tumors in immunocompetent mice relatively more slowly, but unexpectedly, they also formed tumors more slowly in immunodeficient NSG mice. RNA sequencing analysis identified a number of genes involved in autophagy and mTOR signaling that were affected by PD-L1 expression. In support of a functional role, PD-L1 attenuation augmented autophagy and blunted the ability of autophagy inhibitors to limit proliferation in vitro and in vivo in NSG mice. PD-L1 attenuation also reduced mTORC1 activity and augmented the antiproliferative effects of the mTORC1 inhibitor rapamycin. PD-L1lo cells were also relatively deficient in metastasis to the lung, and we found that anti-PD-L1 administration could block tumor cell growth and metastasis in NSG mice. This therapeutic effect was observed with B16 cells but not ID8agg cells, illustrating tumor- or compartmental-specific effects in the therapeutic setting. Overall, our findings extend understanding of PD-L1 functions, illustrate nonimmune effects of anti-PD-L1 immunotherapy, and suggest broader uses for PD-L1 as a biomarker for assessing cancer therapeutic responses. Cancer Res; 76(23); 6964-74. ©2016 AACR., Competing Interests: The authors have no conflicting financial interests to declare., (©2016 American Association for Cancer Research.)- Published
- 2016
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34. Tumor cell-intrinsic PD-L1 promotes tumor-initiating cell generation and functions in melanoma and ovarian cancer.
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Gupta HB, Clark CA, Yuan B, Sareddy G, Pandeswara S, Padron AS, Hurez V, Conejo-Garcia J, Vadlamudi R, Li R, and Curiel TJ
- Abstract
As tumor PD-L1 provides signals to anti-tumor PD-1
+ T cells that blunt their functions, αPD-1 and αPD-L1 antibodies have been developed as anti-cancer immunotherapies based on interrupting this signaling axis. However, tumor cell-intrinsic PD-L1 signals also regulate immune-independent tumor cell proliferation and mTOR signals, among other important effects. Tumor initiating cells (TIC) generate carcinomas, resist treatments and promote relapse. We show here that in murine B16 melanoma and ID8agg ovarian carcinoma cells, TIC express more PD-L1 versus non-TIC. Silencing PD-L1 in B16 and ID8agg cells by shRNA ("PD-L1lo ") reduced TIC numbers, the canonical TIC genes nanog and pou5f1 (oct4), and functions as assessed by tumorosphere development, immune-dependent and immune-independent tumorigenesis, and serial transplantability in vivo . Strikingly, tumor PD-L1 sensitized TIC to interferon-γ and rapamycin in vitro. Cell-intrinsic PD-L1 similarly drove functional TIC generation, canonical TIC gene expression, and sensitivity to interferon-γ and rapamycin in human ES2 ovarian cancer cells. Thus, tumor-intrinsic PD-L1 signals promote TIC generation and virulence, possibly by promoting canonical TIC gene expression, suggesting that PD-L1 has novel signaling effects on cancer pathogenesis and treatment responses., Competing Interests: The authors disclose no potential conflicts of interest- Published
- 2016
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35. Mesothelin expression is associated with poor outcomes in breast cancer.
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Li YR, Xian RR, Ziober A, Conejo-Garcia J, Perales-Puchalt A, June CH, Zhang PJ, and Tchou J
- Subjects
- Adult, Aged, Biomarkers, Tumor genetics, Biomarkers, Tumor metabolism, Breast Neoplasms genetics, Breast Neoplasms pathology, Cohort Studies, Disease-Free Survival, Female, GPI-Linked Proteins genetics, Gene Expression Regulation, Neoplastic, Humans, Kaplan-Meier Estimate, Lymph Nodes pathology, Mesothelin, Middle Aged, Prognosis, Triple Negative Breast Neoplasms genetics, Triple Negative Breast Neoplasms metabolism, Triple Negative Breast Neoplasms mortality, Triple Negative Breast Neoplasms pathology, Breast Neoplasms metabolism, Breast Neoplasms mortality, GPI-Linked Proteins metabolism
- Abstract
Mesothelin is a potential therapeutic target and prognostic marker in breast cancer. However, results on its prognostic value in breast cancer have been equivocal and warranted further evaluation. We analyzed clinical data from two breast cancer patient cohorts comprising of 141 patients treated at our institution (discovery cohort) and 844 patients from The Cancer Genome Atlas (TCGA) (validation cohort). Mesothelin expression was quantified by immunohistochemistry or by RNA transcript levels as measured by whole-transcriptome sequencing in the discovery and validation cohorts respectively. Univariate analyses of data from the discovery cohort demonstrated that tumor size [hazard ratio (HR) = 1.30, 95 % confidence interval (CI) 1.11-1.51], positive (+) axillary lymph nodes (HR = 3.34; 95 % CI 1.51-7.39), and mesothelin expression (HR = 2.03; 95 % CI 1.10-3.74) were associated with disease-specific survival. Multivariate analyses demonstrated that mesothelin expression was significantly associated with worse survival (HR = 3.06, 95 % CI 1.40-6.68) after adjusting for (+) axillary lymph nodes and tumor size. Using TCGA cohort as validation dataset, mesothelin-expressing tumors were indeed significantly associated with worse overall survival with HR = 1.46; 95 % CI 1.05-2.03 and HR = 1.69; 95 % CI 1.17-2.42 in univariate and multivariate analyses respectively. Our results suggest that mesothelin is a prognostic breast tumor marker whose expression is highly enriched in triple negative breast cancer (TNBC) tumors. As there is no existing targeted therapy for TNBC, mesothelin may be a promising drug target for TNBC. Future work is needed to evaluate the efficacy of mesothelin directed targeted therapy in the treatment of breast cancer.
- Published
- 2014
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36. Fibroblast activation protein, a potential diagnostic and therapeutic target for cancer-reply.
- Author
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Tchou J and Conejo-Garcia J
- Subjects
- Female, Humans, Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Gelatinases metabolism, Membrane Proteins metabolism, Serine Endopeptidases metabolism
- Published
- 2014
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37. Fibroblast activation protein expression by stromal cells and tumor-associated macrophages in human breast cancer.
- Author
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Tchou J, Zhang PJ, Bi Y, Satija C, Marjumdar R, Stephen TL, Lo A, Chen H, Mies C, June CH, Conejo-Garcia J, and Puré E
- Subjects
- Actins metabolism, Adult, Aged, Breast Neoplasms pathology, Breast Neoplasms therapy, Cohort Studies, Endopeptidases, Female, Flow Cytometry, Humans, Immunohistochemistry, In Situ Hybridization, Fluorescence, Leukocyte Common Antigens metabolism, Macrophages metabolism, Middle Aged, Prognosis, Stromal Cells metabolism, Biomarkers, Tumor metabolism, Breast Neoplasms metabolism, Gelatinases metabolism, Membrane Proteins metabolism, Serine Endopeptidases metabolism
- Abstract
Fibroblast activation protein (FAP) has long been known to be expressed in the stroma of breast cancer. However, very little is known if the magnitude of FAP expression within the stroma may have a prognostic value and reflect the heterogeneous biology of the tumor cell. An earlier study had suggested that stromal FAP expression in breast cancer was inversely proportional to prognosis. We, therefore, hypothesized that stromal FAP expression may correlate with clinicopathologic variables and may serve as an adjunct prognostic factor in breast cancer. We evaluated the expression of FAP in a panel of breast cancer tissues (n = 52) using a combination of immunostain analyses at the tissue and single-cell level using freshly frozen or freshly digested human breast tumor samples, respectively. Our results showed that FAP expression was abundantly expressed in the stroma across all breast cancer subtypes without significant correlation with clinicopathologic factors. We further identified a subset of FAP-positive (or FAP(+)) stromal cells that also expressed CD45, a pan-leukocyte marker. Using freshly dissociated human breast tumor specimens (n = 5), we demonstrated that some of these FAP(+)CD45(+) cells were CD11b(+)CD14(+)MHC-II(+), indicating that they were likely tumor-associated macrophages (TAMs). Although FAP(+)CD45(+) cells have been demonstrated in the mouse tumor stroma, our results demonstrating that human breast TAMs expressed FAP were novel and suggested that existing and future FAP-directed therapy may have dual-therapeutic benefits targeting both stromal mesenchymal cells and immune cells such as TAMs. More work is needed to explore the role of FAP as a potential targetable molecule in breast cancer treatment., (© 2013 Elsevier Inc. All rights reserved.)
- Published
- 2013
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38. Formation of telomeric repeat-containing RNA (TERRA) foci in highly proliferating mouse cerebellar neuronal progenitors and medulloblastoma.
- Author
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Deng Z, Wang Z, Xiang C, Molczan A, Baubet V, Conejo-Garcia J, Xu X, Lieberman PM, and Dahmane N
- Subjects
- Animals, Brain embryology, Brain pathology, Cell Proliferation, Cerebellar Neoplasms genetics, Coiled Bodies metabolism, DNA Damage, Disease Models, Animal, Gene Expression Regulation, Neoplastic, Hedgehog Proteins pharmacology, Histones metabolism, Humans, In Situ Hybridization, Fluorescence, Interphase, Mice, Models, Biological, Neural Stem Cells pathology, Cerebellar Neoplasms pathology, Medulloblastoma genetics, Medulloblastoma pathology, Neural Stem Cells metabolism, RNA genetics, Repetitive Sequences, Nucleic Acid genetics, Telomere genetics
- Abstract
Telomeres play crucial roles in the maintenance of genome integrity and control of cellular senescence. Most eukaryotic telomeres can be transcribed to generate a telomeric repeat-containing RNA (TERRA) that persists as a heterogeneous nuclear RNA and can be developmentally regulated. However, the precise function and regulation of TERRA in normal and cancer cell development remains poorly understood. Here, we show that TERRA accumulates in highly proliferating normal and cancer cells, and forms large nuclear foci, which are distinct from previously characterized markers of DNA damage or replication stress. Using a mouse model for medulloblastoma driven by chronic Sonic hedgehog (SHH) signaling, TERRA RNA was detected in tumor, but not adjacent normal cells using both RNA fluorescence in situ hybridization (FISH) and northern blotting. RNA FISH revealed the formation of TERRA foci (TERFs) in the nuclear regions of rapidly proliferating tumor cells. In the normal developing cerebellum, TERRA aggregates could also be detected in highly proliferating zones of progenitor neurons. SHH could enhance TERRA expression in purified granule progenitor cells in vitro, suggesting that proliferation signals contribute to TERRA expression in responsive tissue. TERRA foci did not colocalize with γH2AX foci, promyelocytic leukemia (PML) or Cajal bodies in mouse tumor tissue. We also provide evidence that TERRA is elevated in a variety of human cancers. These findings suggest that elevated TERRA levels reflect a novel early form of telomere regulation during replication stress and cancer cell evolution, and the TERRA RNA aggregates may form a novel nuclear body in highly proliferating mammalian cells.
- Published
- 2012
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39. Mesothelin, a novel immunotherapy target for triple negative breast cancer.
- Author
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Tchou J, Wang LC, Selven B, Zhang H, Conejo-Garcia J, Borghaei H, Kalos M, Vondeheide RH, Albelda SM, June CH, and Zhang PJ
- Subjects
- Adoptive Transfer, Antigens, Neoplasm metabolism, Breast Neoplasms genetics, Cell Line, Tumor, Cohort Studies, Female, GPI-Linked Proteins metabolism, Humans, Mesothelin, Receptor, ErbB-2 deficiency, Receptors, Estrogen deficiency, Receptors, Progesterone deficiency, T-Lymphocytes immunology, T-Lymphocytes metabolism, Transduction, Genetic, Antigens, Neoplasm immunology, Breast Neoplasms immunology, Breast Neoplasms therapy, GPI-Linked Proteins immunology, Immunotherapy
- Abstract
Mesothelin is a cell-surface glycoprotein present on mesothelial cells and elicits T cell responses in a variety of cancers including pancreatic, biliary and ovarian cancer. Breast cancer is not known to express mesothelin. We postulated that mesothelin may be a unique tumor-associated antigen in triple negative breast cancer (TNBC), a less common breast cancer subtype which may have been under-represented in prior studies that characterized mesothelin expression. Therefore, we screened 99 primary breast cancer samples by immunohistochemistry analysis using formalin-fixed paraffin-embedded archival tumor tissues and confirmed that mesothelin was overexpressed in the majority of TNBC (67 %) but only rarely in <5 % ER(+) or Her2-neu(+) breast cancer, respectively. To determine whether mesothelin may be exploited as a novel immunotherapy target in breast cancer, an in vitro cell killing assay was performed to compare the ability of genetically modified T cells expressing a chimeric antibody receptor (CAR) specific for mesothelin (mesoCAR T cells) or non-transduced T cells to kill mesothelin-expressing primary breast cancer cells. A significantly higher anti-tumor cytotoxicity by mesoCAR T cells was observed (31.7 vs. 8.7 %, p < 0.001). Our results suggest that mesothelin has promise as a novel immunotherapy target for TNBC for which effective targeted therapy is lacking to date.
- Published
- 2012
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40. Targeting the tumor stroma as a novel treatment strategy for breast cancer: shifting from the neoplastic cell-centric to a stroma-centric paradigm.
- Author
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Tchou J and Conejo-Garcia J
- Subjects
- Antineoplastic Agents pharmacology, Antineoplastic Agents therapeutic use, Disease Progression, Female, Fibroblasts drug effects, Fibroblasts pathology, Humans, Stromal Cells pathology, Breast Neoplasms drug therapy, Breast Neoplasms pathology, Molecular Targeted Therapy, Stromal Cells drug effects
- Abstract
The lack of targeted therapy for women with triple negative breast cancer demands a "think-outside-the-box" approach in search of novel treatment strategies. Although cancer drug development traditionally focused on targeting the tumor cell cycle, emphasis has recently shifted toward the tumor microenvironment for novel therapeutic and prevention strategies. The tumor microenvironment is a dynamic composite of cells broadly categorized as immune cells and nonimmune cells within a scaffold of extracellular matrix, where tumor cells thrive. Among the various nonimmune cell types, cancer stromal cells have emerged as critical players in promoting tumor proliferation, neovascularization, invasion, and metastasis as well as interacting with immune cells to tilt the equilibrium toward a tolerogenic environment that favors the tumor cells. In view of recent work that demonstrated that the depletion of fibroblast activation protein (FAP) expressing tumor stromal cells resulted in stunted tumor growth and improved response to tumor vaccination, the tumor microenvironment is, therefore, fertile ground for development of novel therapy with the potential of augmenting existing treatment and prevention options. In this review, we will focus on current evidence supporting the role of cancer associated fibroblasts (CAFs), with a special focus on FAP(+) stromal cells, in promoting tumor growth. The role of CAFs in promoting an immunosuppressive environment, which may accelerate tumor progression, will be discussed with the hope that therapeutics developed to target the "generic" tumor microenvironment may be effective for malignancies such as triple negative breast cancer, for which targeted therapy is not available to date, in the future., (Copyright © 2012 Elsevier Inc. All rights reserved.)
- Published
- 2012
- Full Text
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41. Human uterine NK cells interact with uterine macrophages via NKG2D upon stimulation with PAMPs.
- Author
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Basu S, Eriksson M, Pioli PA, Conejo-Garcia J, Mselle TF, Yamamoto S, Wira CR, and Sentman CL
- Subjects
- Adult, CD56 Antigen metabolism, Female, Humans, Interferon-gamma biosynthesis, Killer Cells, Natural drug effects, Lipopolysaccharide Receptors metabolism, Macrophages metabolism, Middle Aged, Poly I-C pharmacology, Toll-Like Receptor 3 immunology, Toll-Like Receptor 3 metabolism, Up-Regulation, Uterus drug effects, Uterus metabolism, Killer Cells, Natural immunology, Macrophages immunology, NK Cell Lectin-Like Receptor Subfamily K immunology, Uterus immunology
- Abstract
Problem: The initiation of an immune response often involves the cooperation of various innate immune cells. In the human endometrium, uterine natural killer (uNK) cells and uterine macrophages are present in significant numbers and in close proximity, yet how they cooperatively respond to infectious challenge is poorly understood., Method of Study: Primary autologous uNK cells and macrophages were co-cultured to determine functional interactions after stimulation with pathogen-associated molecular patterns., Results: After stimulation by polyI:C, human uNK cells interact with autologous uterine macrophages and produce interferon-gamma in an NKG2D-dependent manner. Stimulated primary uterine macrophages up-regulated the expression of MHC Class I chain-related protein A (MICA), but expression of the cognate receptor NKG2D remained unchanged on uNK cells, even in the presence of cytokines., Conclusion: This study demonstrates that the NKG2D-MICA interaction is an important molecular mechanism that is involved in the innate immune response to microbial signals in the human uterine endometrium.
- Published
- 2009
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42. Estradiol regulates MICA expression in human endometrial cells.
- Author
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Basu S, Pioli PA, Conejo-Garcia J, Wira CR, and Sentman CL
- Subjects
- Cell Line, Tumor, Female, GPI-Linked Proteins, Histocompatibility Antigens Class I analysis, Histocompatibility Antigens Class I physiology, Humans, Intercellular Signaling Peptides and Proteins analysis, RNA, Messenger analysis, Endometrium immunology, Estradiol pharmacology, Gene Expression Regulation drug effects, Histocompatibility Antigens Class I genetics
- Abstract
The human endometrium undergoes cyclical changes regulated by sex hormones. Evidence suggests that sex hormones regulate NK cell recruitment into the uterus in large numbers. NKG2D is an activating receptor expressed on human NK cells, gammadelta and CD8 T cells. NKG2D ligands are known to be sensors of cellular "stress". In this study, we investigated whether sex hormones directly regulate expression of NKG2D ligands in the human uterus. Estradiol increased MICA expression on uterine epithelial cells; regulation was estrogen receptor-dependent. Real-time PCR analysis showed that NKG2D ligands MICA and MICB were expressed in the human endometrium. MICA protein was detected primarily on epithelial cells, and greater expression was observed in immunohistochemical analysis of tissues from patients in the secretory phase of the menstrual cycle. Thus, estrogens regulate expression of MICA. These data suggest hormonal regulation of innate immunity and NKG2D-mediated recognition in other tissues and diseases where estrogen may be involved.
- Published
- 2008
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43. Chimeric NKG2D receptor-bearing T cells as immunotherapy for ovarian cancer.
- Author
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Barber A, Zhang T, DeMars LR, Conejo-Garcia J, Roby KF, and Sentman CL
- Subjects
- Animals, Cell Growth Processes immunology, Cell Line, Tumor, Cytokines immunology, Cytokines metabolism, Female, Humans, Interferon-gamma immunology, Interferon-gamma metabolism, Mice, Mice, Inbred C57BL, NK Cell Lectin-Like Receptor Subfamily K, Nuclear Matrix-Associated Proteins biosynthesis, Nuclear Matrix-Associated Proteins immunology, Nucleocytoplasmic Transport Proteins biosynthesis, Nucleocytoplasmic Transport Proteins immunology, Receptors, Natural Killer Cell, T-Lymphocytes metabolism, Immunotherapy, Adoptive methods, Ovarian Neoplasms immunology, Ovarian Neoplasms therapy, Receptors, Immunologic immunology, T-Lymphocytes immunology
- Abstract
Despite advancements in the treatment of ovarian cancer, this disease continues to be a leading cause of cancer death in women. Adoptive transfer of tumor-reactive T cells is a promising antitumor therapy for many cancers. We designed a chimeric receptor linking NKG2D, a natural killer (NK) cell-activating receptor, to the CD3zeta chain of the T-cell receptor to target ovarian tumor cells. Engagement of chimeric NKG2D receptors (chNKG2D) with ligands for NKG2D, which are commonly expressed on tumor cells, leads to T-cell secretion of proinflammatory cytokines and tumor cytotoxicity. In this study, we show that >80% of primary human ovarian cancer samples expressed ligands for NKG2D on the cell surface. The tumor samples expressed MHC class I-related protein A, MICB, and UL-16 binding proteins 1 and 3. ChNKG2D-expressing T cells lysed ovarian cancer cell lines. We show that T cells from ovarian cancer patients that express chNKG2D secreted proinflammatory cytokines when cultured with autologous tumor cells. In addition, we show that chNKG2D T cells can be used therapeutically in a murine model of ovarian cancer. These data indicate that treatment with chNKG2D-expressing T cells is a potential immunotherapy for ovarian cancer.
- Published
- 2007
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44. Structure determination of human and murine beta-defensins reveals structural conservation in the absence of significant sequence similarity.
- Author
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Bauer F, Schweimer K, Klüver E, Conejo-Garcia JR, Forssmann WG, Rösch P, Adermann K, and Sticht H
- Subjects
- Amino Acid Sequence, Animals, Chromatography, Conserved Sequence, Crystallography, X-Ray, Disulfides, Humans, Magnetic Resonance Spectroscopy, Mice, Models, Molecular, Molecular Sequence Data, Peptides chemistry, Protein Conformation, Protein Folding, Protein Structure, Secondary, Protein Structure, Tertiary, Sequence Homology, Amino Acid, beta-Defensins chemistry
- Abstract
Defensins are cationic and cysteine-rich peptides that play a crucial role in the host defense against microorganisms of many organisms by their capability to permeabilize bacterial membranes. The low sequence similarity among the members of the large mammalian beta-defensin family suggests that their antimicrobial activity is largely independent of their primary structure. To investigate to what extent these defensins share a similar fold, the structures of the two human beta-defensins, hBD-1 and hBD-2, as well as those of two novel murine defensins, termed mBD-7 and mBD-8, were determined by nuclear magnetic resonance spectroscopy. All four defensins investigated share a striking similarity on the level of secondary and tertiary structure including the lack of a distinct hydrophobic core, suggesting that the fold is mainly stabilized by the presence of three disulfide bonds. In addition to the overall shape of the molecules, the ratio of solvent-exposed polar and hydrophobic side chains is also very similar among the four defensins investigated. It is significant that beta-defensins do not exhibit a common pattern of charged and hydrophobic residues on the protein surface and that the beta-defensin-specific fold appears to accommodate a wide range of different amino acids at most sequence positions. In addition to the implications for the mode of biological defensin actions, these findings are of particular interest because beta-defensins have been suggested as lead compounds for the development of novel peptide antibiotics for the therapy of infectious diseases.
- Published
- 2001
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45. Real-time quantitative PCR of telomerase mRNA is useful for the differentiation of benign and malignant pancreatic disorders.
- Author
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Büchler P, Conejo-Garcia JR, Lehmann G, Müller M, Emrich T, Reber HA, Büchler MW, and Friess H
- Subjects
- Adult, Aged, Chronic Disease, Diagnosis, Differential, Enzyme-Linked Immunosorbent Assay, Female, Humans, Male, Middle Aged, Pancreas enzymology, Pancreas ultrastructure, Pancreatic Neoplasms enzymology, Pancreatic Neoplasms genetics, Pancreatitis enzymology, Reference Values, Telomere ultrastructure, Tumor Cells, Cultured, Pancreatic Neoplasms diagnosis, Pancreatitis diagnosis, Polymerase Chain Reaction, RNA, Messenger analysis, Telomerase genetics
- Abstract
The presence of telomerase activity has been proposed as a specific and sensitive marker for malignant tissue, and positivity rates of up to 95% have been reported in pancreatic cancer. In the present study telomerase activity analysis was reevaluated in 29 pancreatic cancer tissues compared with 36 chronic pancreatitis tissues and 21 normal controls, and a study was made of whether malignant and benign pancreatic disorders can be better differentiated using a novel technique real-time quantitative PCR analysis-analyzing telomerase mRNA expression. Telomerase activity was present in 35% (10 of 29) of pancreatic cancer samples, 3% (one of 36) of chronic pancreatitis samples, and none of the normal pancreatic tissue samples in the TRAP assay. Real-time quantitative PCR analysis revealed the presence of telomerase mRNA expression in 50% (10 of 20) of normal, 86% (31 of 36) of chronic pancreatitis, and 90% (26 of 29) of pancreatic cancer samples. However, quantification of the expression data revealed that the relative increase above normal was 5.5 (range, 3.5-8.6) for chronic pancreatitis and 23.9 (range, 18.6-30.7) for pancreatic cancer samples (p < 0.01). No relationship was found between telomerase activity and the fold increase of telomerase mRNA above normal and gender, patient age, tumor stage, or tumor grade. These data indicate that detection of telomerase activity using the TRAP assay has limitations in differentiating benign and malignant pancreatic disorders. However, telomerase mRNA analysis by real-time quantitative PCR analysis allows a highly sensitive detection and differentiation of pancreatic cancer from normal pancreas and chronic pancreatitis and thereby may serve as a new reliable, easy, and effective diagnostic tool for cancer diagnosis.
- Published
- 2001
- Full Text
- View/download PDF
46. Macrophages infiltrating the tissue in chronic pancreatitis express the chemokine receptor CCR5.
- Author
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Goecke H, Forssmann U, Uguccioni M, Friess H, Conejo-Garcia JR, Zimmermann A, Baggiolini M, and Büchler MW
- Subjects
- Adult, Antigens, CD metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Blotting, Northern, CD3 Complex metabolism, Chemokine CCL3, Chemokine CCL4, Chemokine CCL5 metabolism, Chronic Disease, Female, Humans, Immunohistochemistry, Macrophage Inflammatory Proteins metabolism, Macrophages metabolism, Male, Middle Aged, Pancreas metabolism, Pancreas pathology, Reference Values, Macrophages physiology, Pancreatitis metabolism, Pancreatitis pathology, Receptors, CCR5 metabolism
- Abstract
Background: The immunologic mechanisms involved in the development of chronic pancreatitis (CP) are poorly understood. Chronically inflamed tissues contain increased numbers of mononuclear cells expressing the CC chemokine receptor 5 (CCR5), which is also a coreceptor for HIV entry of macrophagetropic strains. However, whether this receptor is involved in the inflammatory process in CP is not known. In the current study, we analyzed the expression of CCR5 in CP. The detection of chemokine receptors on inflammatory cells would strongly suggest their involvement in the pathogenesis of CP (i.e., attraction and activation of these cells). To further evaluate this, we consecutively analyzed the expression of 2 ligands of CCR5: RANTES and MIP-alpha., Methods: Pancreatic tissue samples of 22 patients with CP and of 7 healthy pancreas were evaluated. CCR5, RANTES, and MIP-1alpha were analyzed by Northern blot analysis. Consecutive tissue sections were stained for CCR5, CD3, and CD68 to define the leukocyte subtype expressing CCR5 in CP., Results: By Northern blot analysis, CCR5, RANTES, and MIP-1alpha messenger RNA (mRNA) levels were 12.9-fold, 13.3-fold and 9.2-fold higher in CP specimens compared with healthy controls, respectively (P<.01). Immunostaining for CCR5 revealed a 30-fold increase of CCR5-positive cells in CP tissue compared with the healthy pancreas. Staining of consecutive tissue sections revealed that the majority of CCR5-positive cells were also CD68-positive (macrophages)., Conclusions: Our data indicate that a remarkable portion of CCR5-positive cells in CP are macrophages. CCR5 is most likely involved in the attraction and activation of these macrophages, since the CCR5 ligands RANTES and MIP-1alpha are concomitantly upregulated.
- Published
- 2000
- Full Text
- View/download PDF
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