100 results on '"Rautela, J."'
Search Results
2. Therapeutic inhibition of the SRC-kinase HCK facilitates T cell tumor infiltration and improves response to immunotherapy
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Poh, AR, Love, CG, Chisanga, D, Steer, JH, Baloyan, D, Chopin, M, Nutt, S, Rautela, J, Huntington, ND, Etemadi, N, O'Brien, M, O'Keefe, R, Ellies, LG, Macri, C, Mintern, JD, Whitehead, L, Gangadhara, G, Boon, L, Chand, AL, Lowell, CA, Shi, W, Pixley, FJ, Ernst, M, Poh, AR, Love, CG, Chisanga, D, Steer, JH, Baloyan, D, Chopin, M, Nutt, S, Rautela, J, Huntington, ND, Etemadi, N, O'Brien, M, O'Keefe, R, Ellies, LG, Macri, C, Mintern, JD, Whitehead, L, Gangadhara, G, Boon, L, Chand, AL, Lowell, CA, Shi, W, Pixley, FJ, and Ernst, M more...
- Abstract
Although immunotherapy has revolutionized cancer treatment, many immunogenic tumors remain refractory to treatment. This can be largely attributed to an immunologically "cold" tumor microenvironment characterized by an accumulation of immunosuppressive myeloid cells and exclusion of activated T cells. Here, we demonstrate that genetic ablation or therapeutic inhibition of the myeloid-specific hematopoietic cell kinase (HCK) enables activity of antagonistic anti-programmed cell death protein 1 (anti-PD1), anti-CTLA4, or agonistic anti-CD40 immunotherapies in otherwise refractory tumors and augments response in treatment-susceptible tumors. Mechanistically, HCK ablation reprograms tumor-associated macrophages and dendritic cells toward an inflammatory endotype and enhances CD8+ T cell recruitment and activation when combined with immunotherapy in mice. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts counteracts tumor immunosuppression, improves T cell recruitment, and impairs tumor growth. Collectively, our results suggest that therapeutic targeting of HCK activity enhances response to immunotherapy by simultaneously stimulating immune cell activation and inhibiting the immunosuppressive tumor microenvironment. more...
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- 2022
Catalog
3. On nondifferentiable minimax fractional programming under generalized α-type I invexity
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Mishra, S. K. and Rautela, J. S.
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- 2009
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4. On nonlinear multiple objective fractional programming involving semilocally type-I univex functions
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Mishra, S. K. and Rautela, J. S.
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- 2009
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5. BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia
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Carrington, EM, Louis, C, Kratina, T, Hancock, M, Keenan, CR, Iannarella, N, Allan, RS, Wardak, AZ, Czabotar, PE, Herold, MJ, Schenk, RL, White, CA, D'Silva, D, Yang, Y, Wong, W, Wong, H, Bryant, VL, Huntington, ND, Rautela, J, Sutherland, RM, Zhan, Y, Hansen, J, Duong, N, Lessene, G, Wicks, IP, Lew, AM, Carrington, EM, Louis, C, Kratina, T, Hancock, M, Keenan, CR, Iannarella, N, Allan, RS, Wardak, AZ, Czabotar, PE, Herold, MJ, Schenk, RL, White, CA, D'Silva, D, Yang, Y, Wong, W, Wong, H, Bryant, VL, Huntington, ND, Rautela, J, Sutherland, RM, Zhan, Y, Hansen, J, Duong, N, Lessene, G, Wicks, IP, and Lew, AM more...
- Abstract
Neutrophils help to clear pathogens and cellular debris, but can also cause collateral damage within inflamed tissues. Prolonged neutrophil residency within an inflammatory niche can exacerbate tissue pathology. Using both genetic and pharmacological approaches, we show that BCL-XL is required for the persistence of neutrophils within inflammatory sites in mice. We demonstrate that a selective BCL-XL inhibitor (A-1331852) has therapeutic potential by causing apoptosis in inflammatory human neutrophils ex vivo. Moreover, in murine models of acute and chronic inflammatory disease, it reduced inflammatory neutrophil numbers and ameliorated tissue pathology. In contrast, there was minimal effect on circulating neutrophils. Thus, we show a differential survival requirement in activated neutrophils for BCL-XL and reveal a new therapeutic approach to neutrophil-mediated diseases. more...
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- 2021
6. Mesenchymal stromal cell apoptosis is required for their therapeutic function
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Pang, SHM, D'Rozario, J, Mendonca, S, Bhuvan, T, Payne, NL, Zheng, D, Hisana, A, Wallis, G, Barugahare, A, Powell, D, Rautela, J, Huntington, ND, Dewson, G, Huang, DCS, Gray, DHD, Heng, TSP, Pang, SHM, D'Rozario, J, Mendonca, S, Bhuvan, T, Payne, NL, Zheng, D, Hisana, A, Wallis, G, Barugahare, A, Powell, D, Rautela, J, Huntington, ND, Dewson, G, Huang, DCS, Gray, DHD, and Heng, TSP more...
- Abstract
Multipotent mesenchymal stromal cells (MSCs) ameliorate a wide range of diseases in preclinical models, but the lack of clarity around their mechanisms of action has impeded their clinical utility. The therapeutic effects of MSCs are often attributed to bioactive molecules secreted by viable MSCs. However, we found that MSCs underwent apoptosis in the lung after intravenous administration, even in the absence of host cytotoxic or alloreactive cells. Deletion of the apoptotic effectors BAK and BAX prevented MSC death and attenuated their immunosuppressive effects in disease models used to define MSC potency. Mechanistically, apoptosis of MSCs and their efferocytosis induced changes in metabolic and inflammatory pathways in alveolar macrophages to effect immunosuppression and reduce disease severity. Our data reveal a mode of action whereby the host response to dying MSCs is key to their therapeutic effects; findings that have broad implications for the effective translation of cell-based therapies. more...
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- 2021
7. MA13.04 Harnessing Natural Killer Cells to Treat Metastatic Small Cell Lung Cancer
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Best, S., primary, Hess, J., additional, Souza-Fonseca Guimaraes, F., additional, Kersbergen, A., additional, Hyslop, S., additional, Rautela, J., additional, Huntington, N., additional, and Sutherland, K., additional more...
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- 2021
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8. Tumor cell derived type I IFN stimulates tumor immunosurveillance, suppressing metastasis to bone: P059
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Slaney, C. Y., Bidwell, B. N., Rautela, J., Anderson, R. L., Hertzog, P. J., and Parker, B. S.
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- 2012
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9. Is mesenchymal stromal cell apoptosis necessary for their immunomodulatory capacity?
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Pang, S., primary, D'Rozario, J., additional, Wallis, G., additional, Hisana, A., additional, Bhuvan, T., additional, Payne, N., additional, Powell, D., additional, Rautela, J., additional, Huntington, N., additional, Dewson, G., additional, Huang, D., additional, Gray, D., additional, and Heng, T., additional more...
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- 2020
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10. NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS (vol 217, e20191421, 2020)
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Louis, C, Guimaraes, F, Yang, Y, D'Silva, D, Kratina, T, Dagley, L, Hediyeh-Zadeh, S, Rautela, J, Masters, SL, Davis, MJ, Babon, JJ, Ciric, B, Vivier, E, Alexander, WS, Huntington, ND, Wicks, IP, Louis, C, Guimaraes, F, Yang, Y, D'Silva, D, Kratina, T, Dagley, L, Hediyeh-Zadeh, S, Rautela, J, Masters, SL, Davis, MJ, Babon, JJ, Ciric, B, Vivier, E, Alexander, WS, Huntington, ND, and Wicks, IP more...
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- 2020
11. NK cell-derived GM-CSF potentiates inflammatory arthritis and is negatively regulated by CIS
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Louis, C, Souza-Fonseca-Guimaraes, F, Yang, Y, D'Silva, D, Kratina, T, Dagley, L, Hediyeh-Zadeh, S, Rautela, J, Masters, SL, Davis, MJ, Babon, JJ, Ciric, B, Vivier, E, Alexander, WS, Huntington, ND, Wicks, IP, Louis, C, Souza-Fonseca-Guimaraes, F, Yang, Y, D'Silva, D, Kratina, T, Dagley, L, Hediyeh-Zadeh, S, Rautela, J, Masters, SL, Davis, MJ, Babon, JJ, Ciric, B, Vivier, E, Alexander, WS, Huntington, ND, and Wicks, IP more...
- Abstract
Despite increasing recognition of the importance of GM-CSF in autoimmune disease, it remains unclear how GM-CSF is regulated at sites of tissue inflammation. Using GM-CSF fate reporter mice, we show that synovial NK cells produce GM-CSF in autoantibody-mediated inflammatory arthritis. Synovial NK cells promote a neutrophilic inflammatory cell infiltrate, and persistent arthritis, via GM-CSF production, as deletion of NK cells, or specific ablation of GM-CSF production in NK cells, abrogated disease. Synovial NK cell production of GM-CSF is IL-18-dependent. Furthermore, we show that cytokine-inducible SH2-containing protein (CIS) is crucial in limiting GM-CSF signaling not only during inflammatory arthritis but also in experimental allergic encephalomyelitis (EAE), a murine model of multiple sclerosis. Thus, a cellular cascade of synovial macrophages, NK cells, and neutrophils mediates persistent joint inflammation via production of IL-18 and GM-CSF. Endogenous CIS provides a key brake on signaling through the GM-CSF receptor. These findings shed new light on GM-CSF biology in sterile tissue inflammation and identify several potential therapeutic targets. more...
- Published
- 2020
12. Drug target validation in primary human natural killer cells using CRISPR RNP
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Rautela, J, Surgenor, E, Huntington, ND, Rautela, J, Surgenor, E, and Huntington, ND
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The ability to genetically modify CD8 T cells using viral gene delivery has facilitated the development of next generation of cancer immunotherapies such as chimeric Ag receptor (CAR) T cells engineered to specifically kill tumor cells. Development of immunotherapies targeting NK cells have stalled in part by their resistance to traditional viral gene delivery systems. Here, an efficient approach is described to genetically edit human NK cells by electroporation and CRISPR-Cas9 ribonucleoprotein (RNP) complexes. Electroporation pulse codes and buffer optimization for protein uptake by human NK cells and viability, and the efficiency of this approach over other methods are detailed. To highlight the transformative step this technique will have for NK cell immunotherapy drug discovery, NCR1 and CISH are deleted in primary human NK cells and murine findings are validated on their key roles in regulating NK cell antitumor function. more...
- Published
- 2020
13. Hhex Directly Represses BIM-Dependent Apoptosis to Promote NK Cell Development and Maintenance
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Goh, W, Scheer, S, Jackson, JT, Hediyeh-Zadeh, S, Delconte, RB, Schuster, IS, Andoniou, CE, Rautela, J, Degli-Esposti, MA, Davis, MJ, McCormack, MP, Nutt, SL, Huntington, ND, Goh, W, Scheer, S, Jackson, JT, Hediyeh-Zadeh, S, Delconte, RB, Schuster, IS, Andoniou, CE, Rautela, J, Degli-Esposti, MA, Davis, MJ, McCormack, MP, Nutt, SL, and Huntington, ND more...
- Abstract
Hhex encodes a homeobox transcriptional regulator important for embryonic development and hematopoiesis. Hhex is highly expressed in NK cells, and its germline deletion results in significant defects in lymphoid development, including NK cells. To determine if Hhex is intrinsically required throughout NK cell development or for NK cell function, we generate mice that specifically lack Hhex in NK cells. NK cell frequency is dramatically reduced, while NK cell differentiation, IL-15 responsiveness, and function at the cellular level remain largely normal in the absence of Hhex. Increased IL-15 availability fails to fully reverse NK lymphopenia following conditional Hhex deletion, suggesting that Hhex regulates developmental pathways extrinsic to those dependent on IL-15. Gene expression and functional genetic approaches reveal that Hhex regulates NK cell survival by directly binding Bcl2l11 (Bim) and repressing expression of this key apoptotic mediator. These data implicate Hhex as a transcriptional regulator of NK cell homeostasis and immunity. more...
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- 2020
14. NK Cell Priming From Endogenous Homeostatic Signals Is Modulated by CIS
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Delconte, RB, Guittard, G, Goh, W, Hediyeh-Zadeh, S, Hennessy, RJ, Rautela, J, Davis, MJ, Souza-Fonseca-Guimaraes, F, Nunes, JA, Huntington, ND, Delconte, RB, Guittard, G, Goh, W, Hediyeh-Zadeh, S, Hennessy, RJ, Rautela, J, Davis, MJ, Souza-Fonseca-Guimaraes, F, Nunes, JA, and Huntington, ND more...
- Abstract
Natural killer (NK) cell activation is controlled by a balance of activating and inhibitory signals and cytokines such as IL-15. We previously identified cytokine-inducible SH2-containing protein (CIS) as a negative regulator of IL-15 signaling in NK cells under inflammatory conditions. While the functional effect of Cish-deficiency in NK cells was obvious by their increased anti-tumor immunity and hyper-proliferative response to IL-15, it remained unclear how CIS regulates NK cell biology in steady-state. Here, we investigated the role of CIS in the homeostatic maintenance of NK cells and found CIS-ablation promoted terminal differentiation of NK cells and increased turnover, suggesting that under steady-state conditions, CIS plays a role in maintaining IL-15 driven regulation of NK cells in vivo. However, hyper-responsiveness to IL-15 did not manifest in NK cell accumulation, even when the essential NK cell apoptosis mediator, Bcl2l11 (BIM) was deleted in addition to Cish. Instead, loss of CIS conferred a lower activation threshold, evidenced by augmented functionality on a per cell basis both in vitro and in vivo without prior priming. We conclude that Cish regulates IL-15 signaling in NK cells in vivo, and through the rewiring of several activation pathways leads to a reduction in activation threshold, decreasing the requirement for priming and improving NK cell anti-tumor function. Furthermore, this study highlights the tight regulation of NK cell homeostasis by several pathways which prevent NK cell accumulation when IL-15 signaling and intrinsic apoptosis are dysregulated. more...
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- 2020
15. Dissecting the molecular pathways of apoptosis in mesenchymal stromal cell therapy
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Pang, S., primary, Wallis, G., additional, Mendonca, S., additional, Hisana, A., additional, Chappaz, S., additional, Rautela, J., additional, Huang, D., additional, Huntington, N., additional, Kile, B., additional, Gray, D., additional, and Heng, T., additional more...
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- 2019
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16. IMiDs prime myeloma cells for daratumumab-mediated cytotoxicity through loss of ikaros and aiolos.
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Grigoriadis G., Gong J.-N., Huntington N.D., Shi W., Huang D.C.S., Tellier J., Nutt S.L., Fedele P.L., Willis S.N., Liao Y., Low M.S., Rautela J., Segal D.H., Grigoriadis G., Gong J.-N., Huntington N.D., Shi W., Huang D.C.S., Tellier J., Nutt S.L., Fedele P.L., Willis S.N., Liao Y., Low M.S., Rautela J., and Segal D.H. more...
- Abstract
Recent studies have demonstrated that the immunomodulatory drugs (IMiDs) lead to the degradation of the transcription factors Ikaros and Aiolos. However, why their loss subsequently leads to multiple myeloma (MM) cell death remains unclear. Using CRISPR-Cas9 genome editing, we have deleted IKZF1/Ikaros and IKZF3/Aiolos in human MM cell lines to gain further insight into their downstream gene regulatory networks. Inactivation of either factor alone recapitulates the cell intrinsic action of the IMiDs, resulting in cell cycle arrest and induction of apoptosis. Furthermore, evaluation of the transcriptional changes resulting from their loss demonstrates striking overlap with lenalidomide treatment. This was not dependent on reduction of the IRF4-MYC "axis," as neither protein was consistently downregulated, despite cell death occurring, and overexpression of either factor failed to rescue for Ikaros loss. Importantly, Ikaros and Aiolos repress the expression of interferon-stimulated genes (ISGs), including CD38, and their loss led to the activation of an interferon-like response, contributing to MM cell death. Ikaros/Aiolos repressed CD38 expression through interaction with the nucleosome remodeling and deacetylase complex in MM. IMiD-induced loss of Ikaros or treatment with interferon resulted in an upregulation of CD38 surface expression on MM cells, priming for daratumumab-induced NK cell-mediated antibody-dependent cellular cytotoxicity. These results give further insight into the mechanism of action of the IMiDs and provide mechanistic rationale for combination with anti-CD38 monoclonal antibodies. (Blood. 2018;132(20):2166-2178)Copyright © 2018 by The American Society of Hematology. more...
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- 2019
17. Tumor inherent interferon regulators as biomarkers of long-term chemotherapeutic response in TNBC.
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Harris M., Parker B.S., Kumar B., Fox J., White M., Brockwell N.K., Rautela J., Owen K.L., Gearing L.J., Deb S., Harvey K., Spurling A., Zanker D., Chan C.-L., Cumming H.E., Deng N., Zakhour J.M., Duivenvoorden H.M., Robinson T., Ooi C., Thomson J., Potasz N., Swarbrick A., Hertzog P.J., Molloy T.J., Toole S.O., Ganju V., Harris M., Parker B.S., Kumar B., Fox J., White M., Brockwell N.K., Rautela J., Owen K.L., Gearing L.J., Deb S., Harvey K., Spurling A., Zanker D., Chan C.-L., Cumming H.E., Deng N., Zakhour J.M., Duivenvoorden H.M., Robinson T., Ooi C., Thomson J., Potasz N., Swarbrick A., Hertzog P.J., Molloy T.J., Toole S.O., and Ganju V. more...
- Abstract
Patients diagnosed with triple negative breast cancer (TNBC) have an increased risk of rapid metastasis compared to other subtypes. Predicting long-term survival post-chemotherapy in patients with TNBC is difficult, yet enhanced infiltration of tumor infiltrating lymphocytes (TILs) has been associated with therapeutic response and reduced risk of metastatic relapse. Immune biomarkers that predict the immune state of a tumor and risk of metastatic relapse pre- or mid-neoadjuvant chemotherapy are urgently needed to allow earlier implementation of alternate therapies that may reduce TNBC patient mortality. Utilizing a neoadjuvant chemotherapy trial where TNBC patients had sequential biopsies taken, we demonstrate that measurement of T-cell subsets and effector function, specifically CD45RO expression, throughout chemotherapy predicts risk of metastatic relapse. Furthermore, we identified the tumor inherent interferon regulatory factor IRF9 as a marker of active intratumoral type I and II interferon (IFN) signaling and reduced risk of distant relapse. Functional implications of tumor intrinsic IFN signaling were demonstrated using an immunocompetent mouse model of TNBC, where enhanced type I IFN signaling increased anti-tumor immunity and metastasis-free survival post-chemotherapy. Using two independent adjuvant cohorts we were able to validate loss of IRF9 as a poor prognostic biomarker pre-chemotherapy. Thus, IRF9 expression may offer early insight into TNBC patient prognosis and tumor heat, allowing for identification of patients that are unlikely to respond to chemotherapy alone and could benefit from further immune-based therapeutic intervention.Copyright © 2019, The Author(s). more...
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- 2019
18. Tumor inherent interferon regulators as biomarkers of long-term chemotherapeutic response in TNBC
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Brockwell, NK, Rautela, J, Owen, KL, Gearing, LJ, Deb, S, Harvey, K, Spurling, A, Zanker, D, Chan, C-L, Cumming, HE, Deng, N, Zakhour, JM, Duivenvoorden, HM, Robinson, T, Harris, M, White, M, Fox, J, Ooi, C, Kumar, B, Thomson, J, Potasz, N, Swarbrick, A, Hertzog, PJ, Molloy, TJ, O'Toole, S, Ganju, V, Parker, BS, Brockwell, NK, Rautela, J, Owen, KL, Gearing, LJ, Deb, S, Harvey, K, Spurling, A, Zanker, D, Chan, C-L, Cumming, HE, Deng, N, Zakhour, JM, Duivenvoorden, HM, Robinson, T, Harris, M, White, M, Fox, J, Ooi, C, Kumar, B, Thomson, J, Potasz, N, Swarbrick, A, Hertzog, PJ, Molloy, TJ, O'Toole, S, Ganju, V, and Parker, BS more...
- Abstract
Patients diagnosed with triple negative breast cancer (TNBC) have an increased risk of rapid metastasis compared to other subtypes. Predicting long-term survival post-chemotherapy in patients with TNBC is difficult, yet enhanced infiltration of tumor infiltrating lymphocytes (TILs) has been associated with therapeutic response and reduced risk of metastatic relapse. Immune biomarkers that predict the immune state of a tumor and risk of metastatic relapse pre- or mid-neoadjuvant chemotherapy are urgently needed to allow earlier implementation of alternate therapies that may reduce TNBC patient mortality. Utilizing a neoadjuvant chemotherapy trial where TNBC patients had sequential biopsies taken, we demonstrate that measurement of T-cell subsets and effector function, specifically CD45RO expression, throughout chemotherapy predicts risk of metastatic relapse. Furthermore, we identified the tumor inherent interferon regulatory factor IRF9 as a marker of active intratumoral type I and II interferon (IFN) signaling and reduced risk of distant relapse. Functional implications of tumor intrinsic IFN signaling were demonstrated using an immunocompetent mouse model of TNBC, where enhanced type I IFN signaling increased anti-tumor immunity and metastasis-free survival post-chemotherapy. Using two independent adjuvant cohorts we were able to validate loss of IRF9 as a poor prognostic biomarker pre-chemotherapy. Thus, IRF9 expression may offer early insight into TNBC patient prognosis and tumor heat, allowing for identification of patients that are unlikely to respond to chemotherapy alone and could benefit from further immune-based therapeutic intervention. more...
- Published
- 2019
19. Quantifying NK cell growth and survival changes in response to cytokines and regulatory checkpoint blockade helps identify optimal culture and expansion conditions
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Hennessy, RJ, Pham, K, Delconte, R, Rautela, J, Hodgkin, PD, Huntington, ND, Hennessy, RJ, Pham, K, Delconte, R, Rautela, J, Hodgkin, PD, and Huntington, ND
- Abstract
NK cells are innate lymphocytes critical for immune surveillance, particularly in eradication of metastatic cancer cells and acute antiviral responses. In contrast to T cells, NK cell-mediated immunity is rapid, with spontaneous cytotoxicity and cytokine/chemokine production upon pathogen detection. The renaissance in cancer immunology has cast NK cell biology back into the spotlight with an urgent need for deeper understanding of the regulatory networks that govern NK cell antitumor activity. To this end, we have adapted and refined a series of quantitative cellular calculus methods, previously applied to T and B lymphocytes, to dissect the biologic outcomes of NK cells following stimulation with cytokines (IL-15, IL-12, IL-18) or deletion of genes that regulate NK cell proliferation (Cish), survival (Bcl2l11), and activation-induced-cell-death (AICD; Fas). Our methodology is well suited to delineate effects on division rate, intrinsic apoptosis, and AICD, permitting variables such as population half-life, rate of cell division, and their combined influence on population numbers in response to stimuli to be accurately measured and modelled. Changes in these variables that result from gene deletion, concentration of stimuli, time, and cell density give insight into the dynamics of NK cell responses and serve as a platform to dissect the mechanism of action of putative checkpoints in NK cell activation and novel NK cell immunotherapy agents. more...
- Published
- 2019
20. The immunomodulatory drugs, through loss of Ikaros and Aiolos, derepress CD38 and functionally synergise with daratumumab.
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Gong J., Huntington N., Shi W., Huang D., Grigoriadis G., Tellier J., Nutt S., Liao Y., Willis S., Low M.S., Rautela J., Segal D.H., Fedele P.L., Gong J., Huntington N., Shi W., Huang D., Grigoriadis G., Tellier J., Nutt S., Liao Y., Willis S., Low M.S., Rautela J., Segal D.H., and Fedele P.L. more...
- Abstract
The transcription factors Ikaros (IKZF1) and Aiolos (IKZF3) have recently been found to be targeted for destruction by the immunomodulatory drugs (IMiDs). However, the role of Ikaros and Aiolos and why their loss leads to multiple myeloma (MM) cell death remains unclear. We have used CRISPRCas9 genome editing to delete IKZF1 and IKZF3 in human MM cell lines to gain further insight into their downstream gene regulatory networks. Consistent with the action of the IMiDs, loss of either of these genes resulted in both a G1/S cell cycle arrest and induction of apoptosis. This was not dependent on the subsequent reduction of the IRF4-MYC "axis", as neither IRF4 or MYC were consistently downregulated across all cell lines examined (despite cell death occurring) and overexpression of either factor failed to rescue for Ikaros loss. This led us to further investigate the transcriptional changes resulting from deletion of Ikaros, Aiolos or treatment with the IMiD lenalidomide using RNA-sequencing. Supporting their central role in the action of the IMiDs, significant overlap was seen on loss of Ikaros, Aiolos, or lenalidomide treatment; with loss of Ikaros/Aiolos accounting for approximately 75% of differential gene expression following lenalidomide. Importantly both Ikaros and Aiolos were found to repress the expression of interferon stimulated genes (ISGs) and their loss led to the activation of an interferon-like response, possibly contributing to cell death. In keeping with this, treatment with lenalidomide and low dose IFNb resulted in synergistic cell death. Furthermore, CD38 appeared to be both an ISG and repressed target of Ikaros/Aiolos through their interaction with the nucleosome remodelling and deacetylase complex, and its expression is increased at both mRNA and protein level on their loss. Given recent clinical studies have shown improved outcomes with combination treatment with lenalidomide and the anti-CD38 monoclonal antibody daratumumab, we wondered whether th more...
- Published
- 2018
21. GM-CSF Quantity Has a Selective Effect on Granulocytic vs. Monocytic Myeloid Development and Function
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Sun, L, Rautela, J, Delconte, RB, Souza-Fonseca-Guimaraes, F, Carrington, EM, Schenk, RL, Herold, MJ, Huntington, ND, Lew, AM, Xu, Y, Zhan, Y, Sun, L, Rautela, J, Delconte, RB, Souza-Fonseca-Guimaraes, F, Carrington, EM, Schenk, RL, Herold, MJ, Huntington, ND, Lew, AM, Xu, Y, and Zhan, Y more...
- Abstract
GM-CSF promotes myeloid differentiation of cultured bone marrow cells into cells of the granulocytic and monocytic lineage; the latter can further differentiate into monocytes/macrophages and dendritic cells. How GM-CSF selects for these different myeloid fates is unresolved. GM-CSF levels can change either iatrogenically (e.g., augmenting leukopoiesis after radiotherapy) or naturally (e.g., during infection or inflammation) resulting in different immunological outcomes. Therefore, we asked whether the dose of GM-CSF may regulate the development of three types of myeloid cells. Here, we showed that GM-CSF acted as a molecular rheostat where the quantity determined which cell type was favored; moreover, the cellular process by which this was achieved was different for each cell type. Thus, low quantities of GM-CSF promoted the granulocytic lineage, mainly through survival. High quantities promoted the monocytic lineage, mainly through proliferation, whereas moderate quantities promoted moDCs, mainly through differentiation. Finally, we demonstrated that monocytes/macrophages generated with different doses of GM-CSF differed in function. We contend that this selective effect of GM-CSF dose on myeloid differentiation and function should be taken into consideration during pathophysiological states that may alter GM-CSF levels and during GM-CSF agonistic or antagonistic therapy. more...
- Published
- 2018
22. Molecular insight into targeting the NK cell immune response to cancer
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Rautela, J, Souza-Fonseca-Guimaraes, F, Hediyeh-Zadeh, S, Delconte, RB, Davis, MJ, Huntington, ND, Rautela, J, Souza-Fonseca-Guimaraes, F, Hediyeh-Zadeh, S, Delconte, RB, Davis, MJ, and Huntington, ND more...
- Abstract
Natural Killer (NK) cells have long been considered an important part of the anti-tumor immune response due to their potent cytolytic and cytokine-secreting abilities. To date, a clear demonstration of the role NK cells play in human cancer is lacking, and there are still very few examples of therapies that efficiently exploit or enhance the spontaneous ability of NK cells to destroy the autologous cancer cells. Given the paradigm shift toward cancer immunotherapy over the past decade, there is a renewed push to understand how NK cell homeostasis and function are regulated in order to therapeutically harness these cells to treat cancer. This review will highlight recent advancements in our understanding of how growth factors impact on NK cell development, differentiation, survival and function with an emphasis on how these pathways may influence NK cell activity in the tumor microenvironment and control of cancer metastasis. more...
- Published
- 2018
23. Myoepithelial cell-specific expression of stefin A as a suppressor of early breast cancer invasion
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Duivenvoorden, HM, Rautela, J, Edgington-Mitchell, LE, Spurling, A, Greening, DW, Nowell, CJ, Molloy, TJ, Robbins, E, Brockwell, NK, Lee-, CS, Chen, M, Holliday, A, Selinger, CI, Hu, M, Britt, KL, Stroud, DA, Bogyo, M, Moeller, A, Polyak, K, Sloane, BF, O'Toole, SA, Parker, BS, Duivenvoorden, HM, Rautela, J, Edgington-Mitchell, LE, Spurling, A, Greening, DW, Nowell, CJ, Molloy, TJ, Robbins, E, Brockwell, NK, Lee-, CS, Chen, M, Holliday, A, Selinger, CI, Hu, M, Britt, KL, Stroud, DA, Bogyo, M, Moeller, A, Polyak, K, Sloane, BF, O'Toole, SA, and Parker, BS more...
- Abstract
Mammography screening has increased the detection of early pre-invasive breast cancers, termed ductal carcinoma in situ (DCIS), increasing the urgency of identifying molecular regulators of invasion as prognostic markers to predict local relapse. Using the MMTV-PyMT breast cancer model and pharmacological protease inhibitors, we reveal that cysteine cathepsins have important roles in early-stage tumorigenesis. To characterize the cell-specific roles of cathepsins in early invasion, we developed a DCIS-like model, incorporating an immortalized myoepithelial cell line (N1ME) that restrained tumor cell invasion in 3D culture. Using this model, we identified an important myoepithelial-specific function of the cysteine cathepsin inhibitor stefin A in suppressing invasion, whereby targeted stefin A loss in N1ME cells blocked myoepithelial-induced suppression of breast cancer cell invasion. Enhanced invasion observed in 3D cultures with N1ME stefin A-low cells was reliant on cathepsin B activation, as addition of the small molecule inhibitor CA-074 rescued the DCIS-like non-invasive phenotype. Importantly, we confirmed that stefin A was indeed abundant in myoepithelial cells in breast tissue. Use of a 138-patient cohort confirmed that myoepithelial stefin A (cystatin A) is abundant in normal breast ducts and low-grade DCIS but reduced in high-grade DCIS, supporting myoepithelial stefin A as a candidate marker of lower risk of invasive relapse. We have therefore identified myoepithelial cell stefin A as a suppressor of early tumor invasion and a candidate marker to distinguish patients who are at low risk of developing invasive breast cancer, and can therefore be spared further treatment. Copyright © 2017 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd. more...
- Published
- 2017
24. Cell cycle progression dictates the requirement for BCL2 in natural killer cell survival
- Author
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Viant, C, Guia, S, Hennessy, RJ, Rautela, J, Pham, K, Bernat, C, Goh, W, Jiao, Y, Delconte, R, Roger, M, Simon, V, Souza-Fonseca-Guimaraes, F, Grabow, S, Belz, GT, Kile, BT, Strasser, A, Gray, D, Hodgkin, PD, Beutler, B, Vivier, E, Ugolini, S, Huntington, ND, Viant, C, Guia, S, Hennessy, RJ, Rautela, J, Pham, K, Bernat, C, Goh, W, Jiao, Y, Delconte, R, Roger, M, Simon, V, Souza-Fonseca-Guimaraes, F, Grabow, S, Belz, GT, Kile, BT, Strasser, A, Gray, D, Hodgkin, PD, Beutler, B, Vivier, E, Ugolini, S, and Huntington, ND more...
- Abstract
Natural killer (NK) cells are innate lymphoid cells with antitumor functions. Using an N-ethyl-N-nitrosourea (ENU)-induced mutagenesis screen in mice, we identified a strain with an NK cell deficiency caused by a hypomorphic mutation in the Bcl2 (B cell lymphoma 2) gene. Analysis of these mice and the conditional deletion of Bcl2 in NK cells revealed a nonredundant intrinsic requirement for BCL2 in NK cell survival. In these mice, NK cells in cycle were protected against apoptosis, and NK cell counts were restored in inflammatory conditions, suggesting a redundant role for BCL2 in proliferating NK cells. Consistent with this, cycling NK cells expressed higher MCL1 (myeloid cell leukemia 1) levels in both control and BCL2-null mice. Finally, we showed that deletion of BIM restored survival in BCL2-deficient but not MCL1-deficient NK cells. Overall, these data demonstrate an essential role for the binding of BCL2 to BIM in the survival of noncycling NK cells. They also favor a model in which MCL1 is the dominant survival protein in proliferating NK cells. more...
- Published
- 2017
25. Cysteine cathepsin activity suppresses osteoclastogenesis of myeloid-derived suppressor cells in breast cancer
- Author
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Edgington-Mitchell, L.E., Rautela, J., Duivenvoorden, H.M., Jayatilleke, K.M., Linden, W.A. van der, Verdoes, M., Bogyo, M., Parker, B.S., Edgington-Mitchell, L.E., Rautela, J., Duivenvoorden, H.M., Jayatilleke, K.M., Linden, W.A. van der, Verdoes, M., Bogyo, M., and Parker, B.S. more...
- Abstract
Contains fulltext : 152094.pdf (Publisher’s version ) (Open Access), Cysteine cathepsin proteases contribute to many normal cellular functions, and their aberrant activity within various cell types can contribute to many diseases, including breast cancer. It is now well accepted that cathepsin proteases have numerous cell-specific functions within the tumor microenvironment that function to promote tumor growth and invasion, such that they may be valid targets for anti-metastatic therapeutic approaches. Using activity-based probes, we have examined the activity and expression of cysteine cathepsins in a mouse model of breast cancer metastasis to bone. In mice bearing highly metastatic tumors, we detected abundant cysteine cathepsin expression and activity in myeloid-derived suppressor cells (MDSCs). These immature immune cells have known metastasis-promoting roles, including immunosuppression and osteoclastogenesis, and we assessed the contribution of cysteine cathepsins to these functions. Blocking cysteine cathepsin activity with multiple small-molecule inhibitors resulted in enhanced differentiation of multinucleated osteoclasts. This highlights a potential role for cysteine cathepsin activity in suppressing the fusion of osteoclast precursor cells. In support of this hypothesis, we found that expression and activity of key cysteine cathepsins were downregulated during MDSC-osteoclast differentiation. Another cysteine protease, legumain, also inhibits osteoclastogenesis, in part through modulation of cathepsin L activity. Together, these data suggest that cysteine protease inhibition is associated with enhanced osteoclastogenesis, a process that has been implicated in bone metastasis. more...
- Published
- 2015
26. Cysteine cathepsin activity suppresses osteoclastogenesis of myeloid-derived suppressor cells in breast cancer
- Author
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Edgington-Mitchell, LE, Rautela, J, Duivenvoorden, HM, Jayatilleke, KM, van der Linden, WA, Verdoes, M, Bogyo, M, Parker, BS, Edgington-Mitchell, LE, Rautela, J, Duivenvoorden, HM, Jayatilleke, KM, van der Linden, WA, Verdoes, M, Bogyo, M, and Parker, BS more...
- Abstract
Cysteine cathepsin proteases contribute to many normal cellular functions, and their aberrant activity within various cell types can contribute to many diseases, including breast cancer. It is now well accepted that cathepsin proteases have numerous cell-specific functions within the tumor microenvironment that function to promote tumor growth and invasion, such that they may be valid targets for anti-metastatic therapeutic approaches. Using activity-based probes, we have examined the activity and expression of cysteine cathepsins in a mouse model of breast cancer metastasis to bone. In mice bearing highly metastatic tumors, we detected abundant cysteine cathepsin expression and activity in myeloid-derived suppressor cells (MDSCs). These immature immune cells have known metastasis-promoting roles, including immunosuppression and osteoclastogenesis, and we assessed the contribution of cysteine cathepsins to these functions. Blocking cysteine cathepsin activity with multiple small-molecule inhibitors resulted in enhanced differentiation of multinucleated osteoclasts. This highlights a potential role for cysteine cathepsin activity in suppressing the fusion of osteoclast precursor cells. In support of this hypothesis, we found that expression and activity of key cysteine cathepsins were downregulated during MDSC-osteoclast differentiation. Another cysteine protease, legumain, also inhibits osteoclastogenesis, in part through modulation of cathepsin L activity. Together, these data suggest that cysteine protease inhibition is associated with enhanced osteoclastogenesis, a process that has been implicated in bone metastasis. more...
- Published
- 2015
27. S-20
- Author
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Rautela, J., primary, Baschuk, N., additional, Jayatilleke, K., additional, Hertzog, P., additional, and Parker, Belinda, additional
- Published
- 2014
- Full Text
- View/download PDF
28. P059 Tumor cell derived type I IFN stimulates tumor immunosurveillance, suppressing metastasis to bone
- Author
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Slaney, C.Y., primary, Bidwell, B.N., additional, Rautela, J., additional, Anderson, R.L., additional, Hertzog, P.J., additional, and Parker, B.S., additional
- Published
- 2012
- Full Text
- View/download PDF
29. On nondifferentiable minimax fractional programming under generalized α-type I invexity
- Author
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Mishra, S. K., primary and Rautela, J. S., additional
- Published
- 2008
- Full Text
- View/download PDF
30. Higher order type-I α-invexity and duality in nondifferentiable mathematical programming
- Author
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Mishra, S. K., primary, Rautela, J. S., additional, and Pant, R. P., additional
- Published
- 2008
- Full Text
- View/download PDF
31. Duality in Vector Optimization Under Type 1 α-Invexity in Banach Spaces
- Author
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Mishra, S. K., primary, Pant, R. P., additional, and Rautela, J. S., additional
- Published
- 2008
- Full Text
- View/download PDF
32. On nonlinear multiple objective fractional programming involving semilocally type-I univex functions
- Author
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Mishra, S. K., primary and Rautela, J. S., additional
- Published
- 2008
- Full Text
- View/download PDF
33. S-20 : Exploiting the type-1 interferon pathway as a biomarker and therapeutic target for metastatic cancer
- Author
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Rautela, J., Baschuk, N., Jayatilleke, K., Hertzog, P., and Parker, Belinda
- Published
- 2014
- Full Text
- View/download PDF
34. Korroosionestomaalausmenetelmien kehittäminen rautatievaunujen valmistuksessa
- Author
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Rautela, J., Teknillinen korkeakoulu, Helsinki University of Technology, Koneinsinööriosasto, Huhtamo, O.E., Lohtari, Lauri, Rautela, J., Teknillinen korkeakoulu, Helsinki University of Technology, Koneinsinööriosasto, Huhtamo, O.E., and Lohtari, Lauri more...
- Published
- 1979
35. Skin-resident memory T cells and melanoma surveillance.
- Author
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Park, S., Buzzai, A., Hochheiser, K., Rautela, J., Hor, J. L., Effern, M., McBain, N., Whitney, P., Mueller, S., Huntington, N., Tuting, T., Herold, M., Holzel, M., Bedoui, S., Mackay, L., Waithman, J., and Gebhardt, T. more...
- Published
- 2017
- Full Text
- View/download PDF
36. Soluble CD52 mediates immune suppression by human seminal fluid.
- Author
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Harrison LC, Stone NL, Bandala-Sanchez E, Huntington ND, McLachlan RI, Rautela J, and O'Bryan MK
- Subjects
- Humans, Male, T-Lymphocytes immunology, T-Lymphocytes metabolism, Antigens, Differentiation, Myelomonocytic metabolism, Antigens, Differentiation, Myelomonocytic immunology, Lectins metabolism, Lectins immunology, Female, Immune Tolerance, HMGB1 Protein, Semen immunology, Semen metabolism, CD52 Antigen metabolism, CD52 Antigen immunology, Killer Cells, Natural immunology, Killer Cells, Natural metabolism
- Abstract
Seminal fluid provides for the carriage and nutrition of sperm, but also modulates immunity to prevent allo-rejection of sperm by the female. Immune suppression by seminal fluid has been associated with extracellular vesicles, originally termed prostasomes, which contain CD52, a glycosylated glycophosphoinositol-anchored peptide released from testicular epithelial cells. Previously, we reported that human T cell-derived CD52, bound to the danger-associated molecular pattern protein, high mobility group box 1 (HMGB1), suppresses T cell function via the inhibitory sialic acid-binding immunoglobulin-like lectin-10 (Siglec-10) receptor. Here we show that human seminal fluid contains high concentrations of CD52 complexed with HMGB1, which mediates T cell suppression indirectly via Siglec-7 on antigen-presenting cells. Proliferation of natural killer (NK) cells, which express Siglec-7 and play a key role in the immune defence of the uterus, was directly suppressed by seminal fluid CD52. These findings elucidate a critical function of seminal fluid to suppress cellular immunity and facilitate reproduction., 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 © 2024 Harrison, Stone, Bandala-Sanchez, Huntington, McLachlan, Rautela and O’Bryan.) more...
- Published
- 2024
- Full Text
- View/download PDF
37. Optimisation of a primary human CAR-NK cell manufacturing pipeline.
- Author
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Pfefferle A, Contet J, Wong K, Chen C, Verhoeyen E, Slichter CK, Schluns KS, Cursons J, Berry R, Nikolic I, Rautela J, and Huntington ND
- Abstract
Objectives: Autologous chimeric antigen receptor (CAR) T-cell therapy of B-cell malignancies achieves long-term disease remission in a high fraction of patients and has triggered intense research into translating this successful approach into additional cancer types. However, the complex logistics involved in autologous CAR-T manufacturing, the compromised fitness of patient-derived T cells, the high rates of serious toxicities and the overall cost involved with product manufacturing and hospitalisation have driven innovation to overcome such hurdles. One alternative approach is the use of allogeneic natural killer (NK) cells as a source for CAR-NK cell therapy. However, this source has traditionally faced numerous manufacturing challenges., Methods: To address this, we have developed an optimised expansion and transduction protocol for primary human NK cells primed for manufacturing scaling and clinical evaluation. We have performed an in-depth comparison of primary human NK cell sources as a starting material by characterising their phenotype, functionality, expansion potential and transduction efficiency at crucial timepoints of our CAR-NK manufacturing pipeline., Results: We identified adult peripheral blood-derived NK cells to be the superior source for generating a CAR-NK cell product because of a higher maximum yield of CAR-expressing NK cells combined with potent natural, as well as CAR-mediated anti-tumor effector functions., Conclusions: Our optimised manufacturing pipeline dramatically improves lentiviral transduction efficiency of primary human NK cells. We conclude that the exponential expansion pre- and post-transduction and high on-target cytotoxicity make peripheral blood-derived NK cells a feasible and attractive CAR-NK cell product for clinical utility., Competing Interests: JC, RB and IN report employment with oNKo‐Innate. NDH, JR, IN, JC and RB report stock or other ownership in oNKo‐Innate. NDH serves on an advisory board for Bristol Myers Squibb and Syena. CKS and KSS report employment with Kite, a Gilead company, and stock or other ownership in Gilead Sciences. KSS serves on the advisor board of Obsidian Therapeutics., (© 2024 The Authors. Clinical & Translational Immunology published by John Wiley & Sons Australia, Ltd on behalf of Australian and New Zealand Society for Immunology, Inc.) more...
- Published
- 2024
- Full Text
- View/download PDF
38. Author Correction: Tumor immunoevasion by the conversion of effector NK cells into type 1 innate lymphoid cell.
- Author
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Gao Y, Souza-Fonseca-Guimaraes F, Bald T, Ng SS, Young A, Ngiow SF, Rautela J, Straube J, Waddell N, Blake SJ, Yan J, Bartholin L, Lee JS, Vivier E, Takeda K, Messaoudene M, Zitvogel L, Teng MWL, Belz GT, Engwerda CR, Huntington ND, Nakamura K, Hölzel M, and Smyth MJ more...
- Published
- 2024
- Full Text
- View/download PDF
39. IKAROS and AIOLOS directly regulate AP-1 transcriptional complexes and are essential for NK cell development.
- Author
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Goh W, Sudholz H, Foroutan M, Scheer S, Pfefferle A, Delconte RB, Meng X, Shen Z, Hennessey R, Kong IY, Schuster IS, Andoniou CE, Davis MJ, Hediyeh-Zadeh S, Souza-Fonseca-Guimaraes F, Parish IA, Beavis P, Thiele D, Chopin M, Degli-Esposti MA, Cursons J, Kallies A, Rautela J, Nutt SL, and Huntington ND more...
- Subjects
- Receptors, Interleukin-15, Ikaros Transcription Factor genetics, Ikaros Transcription Factor metabolism, Transcription Factor AP-1 genetics, Killer Cells, Natural metabolism
- Abstract
Ikaros transcription factors are essential for adaptive lymphocyte function, yet their role in innate lymphopoiesis is unknown. Using conditional genetic inactivation, we show that Ikzf1/Ikaros is essential for normal natural killer (NK) cell lymphopoiesis and IKZF1 directly represses Cish, a negative regulator of interleukin-15 receptor resulting in impaired interleukin-15 receptor signaling. Both Bcl2l11 and BIM levels, and intrinsic apoptosis were increased in Ikzf1-null NK cells, which in part accounts for NK lymphopenia as both were restored to normal levels when Ikzf1 and Bcl2l11 were co-deleted. Ikzf1-null NK cells presented extensive transcriptional alterations with reduced AP-1 transcriptional complex expression and increased expression of Ikzf2/Helios and Ikzf3/Aiolos. IKZF1 and IKZF3 directly bound AP-1 family members and deletion of both Ikzf1 and Ikzf3 in NK cells resulted in further reductions in Jun/Fos expression and complete loss of peripheral NK cells. Collectively, we show that Ikaros family members are important regulators of apoptosis, cytokine responsiveness and AP-1 transcriptional activity., (© 2024. The Author(s), under exclusive licence to Springer Nature America, Inc.) more...
- Published
- 2024
- Full Text
- View/download PDF
40. Author Correction: CIS is a potent checkpoint in NK cell-mediated tumor immunity.
- Author
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Delconte RB, Kolesnik TB, Dagley LF, Rautela J, Shi W, Putz EM, Stannard K, Zhang JG, Teh C, Firth M, Ushiki T, Andoniou CE, Degli-Esposti MA, Sharp PP, Sanvitale CE, Infusini G, Liau NPD, Linossi EM, Burns CJ, Carotta S, Gray DHD, Seillet C, Hutchinson DS, Belz GT, Webb AI, Alexander WS, Li SS, Bullock AN, Babon JJ, Smyth MJ, Nicholson SE, and Huntington ND more...
- Published
- 2024
- Full Text
- View/download PDF
41. CD45 limits early Natural Killer cell development.
- Author
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Meza Guzman LG, Hyland CD, Bidgood GM, Leong E, Shen Z, Goh W, Rautela J, Vince JE, Nicholson SE, and Huntington ND
- Subjects
- Animals, Mice, Immunotherapy, Immunotherapy, Adoptive, Tumor Microenvironment, Killer Cells, Natural, Neoplasms
- Abstract
The clinical development of Natural Killer (NK) cell-mediated immunotherapy marks a milestone in the development of new cancer therapies and has gained traction due to the intrinsic ability of the NK cell to target and kill tumor cells. To fully harness the tumor killing ability of NK cells, we need to improve NK cell persistence and to overcome suppression of NK cell activation in the tumor microenvironment. The trans-membrane, protein tyrosine phosphatase CD45, regulates NK cell homeostasis, with the genetic loss of CD45 in mice resulting in increased numbers of mature NK cells. This suggests that CD45-deficient NK cells might display enhanced persistence following adoptive transfer. However, we demonstrate here that adoptive transfer of CD45-deficiency did not enhance NK cell persistence in mice, and instead, the homeostatic disturbance of NK cells in CD45-deficient mice stemmed from a developmental defect in the progenitor population. The enhanced maturation within the CD45-deficient NK cell compartment was intrinsic to the NK cell lineage, and independent of the developmental defect. CD45 is not a conventional immune checkpoint candidate, as systemic loss is detrimental to T and B cell development, compromising the adaptive immune system. Nonetheless, this study suggests that inhibition of CD45 in progenitor or stem cell populations may improve the yield of in vitro generated NK cells for adoptive therapy., (© 2023 The Authors. Immunology & Cell Biology published by John Wiley & Sons Australia, Ltd on behalf of the Australian and New Zealand Society for Immunology, Inc.) more...
- Published
- 2024
- Full Text
- View/download PDF
42. CIS controls the functional polarization of GM-CSF-derived macrophages.
- Author
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Zhang S, Rautela J, Bediaga NG, Kolesnik TB, You Y, Nie J, Dagley LF, Bedo J, Wang H, Sun L, Sutherland R, Surgenor E, Iannarella N, Allan R, Souza-Fonseca-Guimaraes F, Xie Y, Wang Q, Zhang Y, Xu Y, Nutt SL, Lew AM, Huntington ND, Nicholson SE, Chopin M, and Zhan Y more...
- Subjects
- Monocytes metabolism, Cytokines metabolism, Interferon Regulatory Factors metabolism, Cell Differentiation, Granulocyte-Macrophage Colony-Stimulating Factor pharmacology, Granulocyte-Macrophage Colony-Stimulating Factor metabolism, Macrophages
- Abstract
The cytokine granulocyte-macrophage-colony stimulating factor (GM-CSF) possesses the capacity to differentiate monocytes into macrophages (MØs) with opposing functions, namely, proinflammatory M1-like MØs and immunosuppressive M2-like MØs. Despite the importance of these opposing biological outcomes, the intrinsic mechanism that regulates the functional polarization of MØs under GM-CSF signaling remains elusive. Here, we showed that GM-CSF-induced MØ polarization resulted in the expression of cytokine-inducible SH2-containing protein (CIS) and that CIS deficiency skewed the differentiation of monocytes toward immunosuppressive M2-like MØs. CIS deficiency resulted in hyperactivation of the JAK-STAT5 signaling pathway, consequently promoting downregulation of the transcription factor Interferon Regulatory Factor 8 (IRF8). Loss- and gain-of-function approaches highlighted IRF8 as a critical regulator of the M1-like polarization program. In vivo, CIS deficiency induced the differentiation of M2-like macrophages, which promoted strong Th2 immune responses characterized by the development of severe experimental asthma. Collectively, our results reveal a CIS-modulated mechanism that clarifies the opposing actions of GM-CSF in MØ differentiation and uncovers the role of GM-CSF in controlling allergic inflammation., (© 2022. The Author(s), under exclusive licence to CSI and USTC.) more...
- Published
- 2023
- Full Text
- View/download PDF
43. An Augmented Method for Collecting PLGA Nanoparticles and the Fabrication of 1, 3, 4, 6-Tetra- O -acetyl-2-azido-2-deoxy-D-glucopyranose (Ac 4 2AzGlc)-Loaded PLGA Nanoparticles for Efficient and Prospective in Vivo Metabolic Processing.
- Author
-
Parashar S, Chauhan C, Rajasekharan A, Rautela J, Jain T, and Raza K
- Abstract
We investigated two ways for fabricating 1, 3, 4, 6-tetra- O -acetyl-2-azido-2-deoxy-D-glucopyranose (Ac
4 2AzGlc)-loaded poly (lactic-co-glycolic acid) PLGA nanoparticles in this article : 1) single emulsion solvent evaporation and 2) the nanoprecipitation method. Among the available methods of collecting nanoparticles using an ultra-high-speed centrifuge, we improvised a less-known method for collecting synthesized nanoparticles without a high-speed centrifuge, based on molecular weight (MW)-dependent centrifugal filters. These nanoparticles were collected in a tabletop centrifuge at a meager centrifugal force in the range of 200-300 xg whereas the conventional high-speed centrifuge method for nanoparticle recovery results in a hard nanoparticle pellet with poor resuspendability which hampers the yield and outcomes of the product. The Ac4 2AzGlc-loaded PLGA nanoparticles were spherical in shape with consistent and reliable nanometric particle size. The polydispersity indices were well within the acceptable limits. The preliminary studies in RAW 264.7 cell and C57BL/6 mice advocated efficient engineering in the former; however, the latter needs further confirmatory investigations. Preliminary in vivo studies with un-encapsulated Ac4 2AzGlc showed poor engineering of cardiac glycoproteins, opening up avenues for Ac4 2AzGlc-loaded nanoparticles for improved bioavailability and efficient metabolic engineering., 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 © 2022 Parashar, Chauhan, Rajasekharan, Rautela, Jain and Raza.) more...- Published
- 2022
- Full Text
- View/download PDF
44. Therapeutic inhibition of the SRC-kinase HCK facilitates T cell tumor infiltration and improves response to immunotherapy.
- Author
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Poh AR, Love CG, Chisanga D, Steer JH, Baloyan D, Chopin M, Nutt S, Rautela J, Huntington ND, Etemadi N, O'Brien M, O'Keefe R, Ellies LG, Macri C, Mintern JD, Whitehead L, Gangadhara G, Boon L, Chand AL, Lowell CA, Shi W, Pixley FJ, and Ernst M more...
- Abstract
Although immunotherapy has revolutionized cancer treatment, many immunogenic tumors remain refractory to treatment. This can be largely attributed to an immunologically "cold" tumor microenvironment characterized by an accumulation of immunosuppressive myeloid cells and exclusion of activated T cells. Here, we demonstrate that genetic ablation or therapeutic inhibition of the myeloid-specific hematopoietic cell kinase (HCK) enables activity of antagonistic anti-programmed cell death protein 1 (anti-PD1), anti-CTLA4, or agonistic anti-CD40 immunotherapies in otherwise refractory tumors and augments response in treatment-susceptible tumors. Mechanistically, HCK ablation reprograms tumor-associated macrophages and dendritic cells toward an inflammatory endotype and enhances CD8
+ T cell recruitment and activation when combined with immunotherapy in mice. Meanwhile, therapeutic inhibition of HCK in humanized mice engrafted with patient-derived xenografts counteracts tumor immunosuppression, improves T cell recruitment, and impairs tumor growth. Collectively, our results suggest that therapeutic targeting of HCK activity enhances response to immunotherapy by simultaneously stimulating immune cell activation and inhibiting the immunosuppressive tumor microenvironment. more...- Published
- 2022
- Full Text
- View/download PDF
45. Mesenchymal stromal cell apoptosis is required for their therapeutic function.
- Author
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Pang SHM, D'Rozario J, Mendonca S, Bhuvan T, Payne NL, Zheng D, Hisana A, Wallis G, Barugahare A, Powell D, Rautela J, Huntington ND, Dewson G, Huang DCS, Gray DHD, and Heng TSP
- Subjects
- Animals, Apoptosis genetics, Cell Death genetics, Cells, Cultured, Female, Flow Cytometry, Humans, Immunoblotting, Immunosuppression Therapy, Macrophages, Alveolar metabolism, Mesenchymal Stem Cell Transplantation, Mice, Mice, Inbred BALB C, Mice, Inbred C57BL, Principal Component Analysis, Apoptosis physiology, Cell Death physiology, Mesenchymal Stem Cells metabolism
- Abstract
Multipotent mesenchymal stromal cells (MSCs) ameliorate a wide range of diseases in preclinical models, but the lack of clarity around their mechanisms of action has impeded their clinical utility. The therapeutic effects of MSCs are often attributed to bioactive molecules secreted by viable MSCs. However, we found that MSCs underwent apoptosis in the lung after intravenous administration, even in the absence of host cytotoxic or alloreactive cells. Deletion of the apoptotic effectors BAK and BAX prevented MSC death and attenuated their immunosuppressive effects in disease models used to define MSC potency. Mechanistically, apoptosis of MSCs and their efferocytosis induced changes in metabolic and inflammatory pathways in alveolar macrophages to effect immunosuppression and reduce disease severity. Our data reveal a mode of action whereby the host response to dying MSCs is key to their therapeutic effects; findings that have broad implications for the effective translation of cell-based therapies., (© 2021. The Author(s).) more...
- Published
- 2021
- Full Text
- View/download PDF
46. Differential requirement for the Polycomb repressor complex 2 in dendritic cell and tissue-resident myeloid cell homeostasis.
- Author
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Zhan Y, Zhang Y, Zhang S, Coughlan H, Baldoni PL, Jacquelot N, Cao WHJ, Preston S, Louis C, Rautela J, Pellegrini M, Wicks IP, Alexander WS, Harrison LC, Lew AM, Smyth GK, Nutt SL, and Chopin M
- Subjects
- Animals, Mice, Mice, Inbred C57BL, Mice, Knockout, Mice, Transgenic, Polycomb Repressive Complex 2 deficiency, Dendritic Cells immunology, Homeostasis immunology, Myeloid Cells immunology, Polycomb Repressive Complex 2 immunology
- Abstract
Dendritic cells (DCs) and macrophages are at the forefront of immune responses, modifying their transcriptional programs in response to their tissue environment or immunological challenge. Posttranslational modifications of histones, such as histone H3 lysine-27 trimethylation (H3K27me3) by the Polycomb repressive complex 2 (PRC2), are tightly associated with epigenetic regulation of gene expression. To explore whether H3K27me3 is involved in either the establishment or function of the mononuclear phagocyte system, we selectively deleted core components of PRC2, either EZH2 or SUZ12, in CD11c-expressing myeloid cells. Unexpectedly, EZH2 deficiency neither prevented the deposition and maintenance of H3K27me3 in DCs nor hindered DC/macrophage homeostasis. In contrast, SUZ12 deficiency markedly impaired the capacity of DCs and macrophages to maintain H3K27me3. SUZ12 ablation induced a rapid loss of the alveolar macrophage and Langerhans cell networks under both steady state and inflammatory conditions because these cells could no longer proliferate to facilitate their self-renewal. Despite the reduced H3K27me3, DC development and function were unaffected by SUZ12 ablation, suggesting that PRC2-mediated gene repression was dispensable for DC homeostasis. Thus, the role of SUZ12 highlights the fundamentally different homeostatic mechanisms used by tissue-resident myeloid cells versus DCs. more...
- Published
- 2021
- Full Text
- View/download PDF
47. BCL-XL antagonism selectively reduces neutrophil life span within inflamed tissues without causing neutropenia.
- Author
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Carrington EM, Louis C, Kratina T, Hancock M, Keenan CR, Iannarella N, Allan RS, Wardak AZ, Czabotar PE, Herold MJ, Schenk RL, White CA, D'Silva D, Yang Y, Wong W, Wong H, Bryant VL, Huntington ND, Rautela J, Sutherland RM, Zhan Y, Hansen J, Nhu D, Lessene G, Wicks IP, and Lew AM more...
- Subjects
- Animals, Apoptosis, Longevity, Mice, Neutropenia drug therapy, Neutrophils
- Abstract
Neutrophils help to clear pathogens and cellular debris, but can also cause collateral damage within inflamed tissues. Prolonged neutrophil residency within an inflammatory niche can exacerbate tissue pathology. Using both genetic and pharmacological approaches, we show that BCL-XL is required for the persistence of neutrophils within inflammatory sites in mice. We demonstrate that a selective BCL-XL inhibitor (A-1331852) has therapeutic potential by causing apoptosis in inflammatory human neutrophils ex vivo. Moreover, in murine models of acute and chronic inflammatory disease, it reduced inflammatory neutrophil numbers and ameliorated tissue pathology. In contrast, there was minimal effect on circulating neutrophils. Thus, we show a differential survival requirement in activated neutrophils for BCL-XL and reveal a new therapeutic approach to neutrophil-mediated diseases., (© 2021 by The American Society of Hematology.) more...
- Published
- 2021
- Full Text
- View/download PDF
48. Single-cell analyses reveal the clonal and molecular aetiology of Flt3L-induced emergency dendritic cell development.
- Author
-
Lin DS, Tian L, Tomei S, Amann-Zalcenstein D, Baldwin TM, Weber TS, Schreuder J, Stonehouse OJ, Rautela J, Huntington ND, Taoudi S, Ritchie ME, Hodgkin PD, Ng AP, Nutt SL, and Naik SH
- Subjects
- Animals, Cell Lineage, Cells, Cultured, Dendritic Cells immunology, Dendritic Cells metabolism, Female, Gene Expression Regulation, Developmental, Hematopoietic Stem Cells immunology, Hematopoietic Stem Cells metabolism, Interferon Regulatory Factors genetics, Interferon Regulatory Factors metabolism, Male, Mice, Inbred C57BL, Mice, Transgenic, Phenotype, Mice, Cell Proliferation drug effects, Dendritic Cells drug effects, Hematopoiesis drug effects, Hematopoietic Stem Cells drug effects, Membrane Proteins pharmacology, RNA-Seq, Single-Cell Analysis, Transcriptome drug effects
- Abstract
Regulation of haematopoietic stem and progenitor cell (HSPC) fate is crucial during homeostasis and under stress conditions. Here we examine the aetiology of the Flt3 ligand (Flt3L)-mediated increase of type 1 conventional dendritic cells (cDC1s). Using cellular barcoding we demonstrate this occurs through selective clonal expansion of HSPCs that are primed to produce cDC1s and not through activation of cDC1 fate by other HSPCs. In particular, multi/oligo-potent clones selectively amplify their cDC1 output, without compromising the production of other lineages, via a process we term tuning. We then develop Divi-Seq to simultaneously profile the division history, surface phenotype and transcriptome of individual HSPCs. We discover that Flt3L-responsive HSPCs maintain a proliferative 'early progenitor'-like state, leading to the selective expansion of multiple transitional cDC1-primed progenitor stages that are marked by Irf8 expression. These findings define the mechanistic action of Flt3L through clonal tuning, which has important implications for other models of 'emergency' haematopoiesis. more...
- Published
- 2021
- Full Text
- View/download PDF
49. Hhex Directly Represses BIM-Dependent Apoptosis to Promote NK Cell Development and Maintenance.
- Author
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Goh W, Scheer S, Jackson JT, Hediyeh-Zadeh S, Delconte RB, Schuster IS, Andoniou CE, Rautela J, Degli-Esposti MA, Davis MJ, McCormack MP, Nutt SL, and Huntington ND
- Subjects
- Animals, Apoptosis genetics, Cell Differentiation physiology, Cell Proliferation physiology, Cell Survival physiology, Female, Gene Expression Regulation genetics, Hematopoiesis genetics, Homeodomain Proteins genetics, Homeodomain Proteins physiology, Interleukin-15 genetics, Interleukin-15 immunology, Killer Cells, Natural immunology, Male, Mice, Mice, Inbred C57BL, Signal Transduction physiology, Transcription Factors genetics, Transcription Factors physiology, Homeodomain Proteins metabolism, Killer Cells, Natural metabolism, Transcription Factors metabolism
- Abstract
Hhex encodes a homeobox transcriptional regulator important for embryonic development and hematopoiesis. Hhex is highly expressed in NK cells, and its germline deletion results in significant defects in lymphoid development, including NK cells. To determine if Hhex is intrinsically required throughout NK cell development or for NK cell function, we generate mice that specifically lack Hhex in NK cells. NK cell frequency is dramatically reduced, while NK cell differentiation, IL-15 responsiveness, and function at the cellular level remain largely normal in the absence of Hhex. Increased IL-15 availability fails to fully reverse NK lymphopenia following conditional Hhex deletion, suggesting that Hhex regulates developmental pathways extrinsic to those dependent on IL-15. Gene expression and functional genetic approaches reveal that Hhex regulates NK cell survival by directly binding Bcl2l11 (Bim) and repressing expression of this key apoptotic mediator. These data implicate Hhex as a transcriptional regulator of NK cell homeostasis and immunity., Competing Interests: Declaration of Interests N.D.H. and J.R. are cofounders and shareholders in oNKo-Innate. The other authors declared no competing interests., (Copyright © 2020 The Authors. Published by Elsevier Inc. All rights reserved.) more...
- Published
- 2020
- Full Text
- View/download PDF
50. Drug target validation in primary human natural killer cells using CRISPR RNP.
- Author
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Rautela J, Surgenor E, and Huntington ND
- Subjects
- Animals, Humans, Killer Cells, Natural cytology, Mice, CRISPR-Cas Systems, Drug Discovery, Electroporation, Killer Cells, Natural immunology
- Abstract
The ability to genetically modify CD8 T cells using viral gene delivery has facilitated the development of next generation of cancer immunotherapies such as chimeric Ag receptor (CAR) T cells engineered to specifically kill tumor cells. Development of immunotherapies targeting NK cells have stalled in part by their resistance to traditional viral gene delivery systems. Here, an efficient approach is described to genetically edit human NK cells by electroporation and CRISPR-Cas9 ribonucleoprotein (RNP) complexes. Electroporation pulse codes and buffer optimization for protein uptake by human NK cells and viability, and the efficiency of this approach over other methods are detailed. To highlight the transformative step this technique will have for NK cell immunotherapy drug discovery, NCR1 and CISH are deleted in primary human NK cells and murine findings are validated on their key roles in regulating NK cell antitumor function., (©2020 Society for Leukocyte Biology.) more...
- Published
- 2020
- Full Text
- View/download PDF
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