Search

Common germline variants of the APOE gene are major risk modifiers of neurodegenerative and atherosclerotic diseases.sup.1-3, but their effect on cancer outcome is poorly defined. Here we report that, in a reversal of their effect on Alzheimer's disease, the APOE4 and APOE2 variants confer favorable and poor outcomes in melanoma, respectively. Mice expressing the human APOE4 allele exhibited reduced melanoma progression and metastasis relative to APOE2 mice. APOE4 mice exhibited enhanced anti-tumor immune activation relative to APOE2 mice, and T cell depletion experiments showed that the effect of APOE genotype on melanoma progression was mediated by altered anti-tumor immunity. Consistently, patients with melanoma carrying the APOE4 variant experienced improved survival in comparison to carriers of APOE2. Notably, APOE4 mice also showed improved outcomes under PD1 immune checkpoint blockade relative to APOE2 mice, and patients carrying APOE4 experienced improved anti-PD1 immunotherapy survival after progression on frontline regimens. Finally, enhancing APOE expression via pharmacologic activation of liver X receptors, previously shown to boost anti-tumor immunity.sup.4, exhibited therapeutic efficacy in APOE4 mice but not in APOE2 mice. These findings demonstrate that pre-existing hereditary genetics can impact progression and survival outcomes of a future malignancy and warrant prospective investigation of APOE genotype as a biomarker for melanoma outcome and therapeutic response. Heritable APOE variants in patients with melanoma influence anti-tumor immunity and modulate metastatic progression and response to immunotherapy., Author(s): Benjamin N. Ostendorf [sup.1] , Jana Bilanovic [sup.1] , Nneoma Adaku [sup.1] , Kimia N. Tafreshian [sup.1] , Bernardo Tavora [sup.1] , Roger D. Vaughan [sup.2] , Sohail F. [...]

Recent reports have revealed myelodysplastic syndromes (MDS) to arise from cancer stem cells phenotypically similar to physiological hematopoietic stem cells. Myelodysplastic hematopoiesis maintains a hierarchical organization, but the proportion of several hematopoietic compartments is skewed and multiple surface markers are aberrantly expressed. These aberrant antigen expression patterns hold diagnostic and therapeutic promise. However, eradication of MDS requires targeting of early myelodysplasia propagating stem cells. This warrants an exact assessment of the differentiation stage at which aberrant expression occurs in transformed hematopoiesis. Here, we report results on the prospective and extensive dissection of the hematopoietic hierarchy in 20 patients with either low-risk MDS or MDS with excess blasts and compare it to hematopoiesis in patients with non-malignancy-associated cytopenia or B cell lymphoma without bone marrow infiltration. We found patients with MDS with excess blasts to exhibit characteristic expansions of specific immature progenitor compartments. We also identified the aberrant expression of several markers including ALDH, CLL-1, CD44, and CD47 to be specific features of hematopoiesis in MDS with excess blasts. We show that amongst these, aberrant CLL-1 expression manifested at the early uncommitted hematopoietic stem cell level, suggesting a potential role as a therapeutic target. [ABSTRACT FROM AUTHOR]

The management of patients with chronic myeloid leukemia (CML) in advanced phases is challenging and requires the consideration of different treatment approaches, including targeted therapy with tyrosine kinase inhibitors, cytotoxic chemotherapy, and allogeneic stem cell transplantation. Here, we present the case of a patient with CML in mixed phenotype blast phase illustrating the integration of these strategies and demonstrating the need for close monitoring of treatment response in order to individually adjust treatment regimens. [ABSTRACT FROM AUTHOR]

Patients receiving radiotherapy often experience toxicity of the skin and mucous membranes. While radiotherapy is a mainstay of myeloablative conditioning for allogeneic hematopoietic stem cell transplantation ( ASCT), no risk factors for radiotoxicity have been identified in this setting. Here, we report on a patient with excessive radiation-induced toxicity after ASCT who carried a heterozygous mutation in the Ataxia telangiectasia mutated ( ATM) gene. This is the first case to suggest a genetic basis for increased radiotoxicity after myeloablative ASCT. [ABSTRACT FROM AUTHOR]

Induction of myeloid-derived suppressor cells is an important mechanism leading to tolerance against tumors. Phenotypic characterization of MDSC has been established and heterogeneous populations with monocytic or granulocytic features have been characterized. Increased levels of MDSC have been described in metastatic renal cell carcinoma and seem to correlate with an adverse outcome. As MDSC constitute only small populations in peripheral blood of cancer patients, it is highly important to achieve technically optimized conditions for quantification. Different cell preparation techniques – besides freezing and thawing – are potential sources of substantial variation. Our study was focused on an optimized quantification of MDSC in pB of healthy donors and patients with mRCC, in whom major technical sources of variation were analyzed. Whole blood and peripheral blood mononuclear cells were used for the flow cytometric quantification of MDSC in the pB of mRCC patients and healthy donors. We compared (1) analysis in whole blood vs. PBMC after Ficoll gradient centrifugation and (2) immediate analysis after blood drawing vs. analysis one day later. Finally, in order to evaluate our optimized technical approach, pB of 15 patients with histologically confirmed mRCC under treatment with either sunitinib or sorafenib was analyzed. No difference in the number of MDSC was observed after analysis in whole blood vs. PBMC. In contrast, the time point of analysis was a source of substantial variation (one day later vs. immediate analysis after blood drawing). In conclusion, for optimal analysis of MDSC, immediate analysis of whole blood after blood drawing rather than one day later seems to be most appropriate under the aspect of practical feasibility and reliability. Using this method, we were able to confirm both (a) increased numbers of MDSC in patients with mRCC and (b) a decrease of MDSC under sunitinib therapy. [ABSTRACT FROM AUTHOR]

Metastatic colonization is the primary cause of death from colorectal cancer (CRC). We employed genome-scale in vivo short hairpin RNA (shRNA) screening and validation to identify 26 promoters of CRC liver colonization. Among these genes, we identified a cluster that contains multiple targetable genes, including ITPR3, which promoted liver-metastatic colonization and elicited similar downstream gene expression programs. ITPR3 is a caffeine-sensitive inositol 1,4,5-triphosphate (IP3) receptor that releases calcium from the endoplasmic reticulum and enhanced metastatic colonization by inducing expression of RELB, a transcription factor that is associated with non-canonical NF-κB signaling. Genetic, cell biological, pharmacologic, and clinical association studies revealed that ITPR3 and RELB drive CRC colony formation by promoting cell survival upon substratum detachment or hypoxic exposure. RELB was sufficient to drive colonization downstream of ITPR3. Our findings implicate the ITPR3/calcium/RELB axis in CRC metastatic colony formation and uncover multiple clinico-pathologically associated targetable proteins as drivers of CRC metastatic colonization. [Display omitted] • Loss of ITPR3 in colorectal cancer cells inhibits metastatic liver colonization • RELB acts downstream of ITPR3/calcium to promote colorectal cancer liver metastasis • ITPR3 and RELB regulate survival in response to hypoxia and substratum detachment • Exposure of colorectal cancer cells to ITPR3 inhibitor caffeine reduces liver metastasis Moy et al. define a clinically relevant pathway that promotes colorectal cancer cell survival and liver metastasis via the type 3 inositol 1,4,5-triphosphate receptor ITPR3, a calcium channel that controls calcium release from the endoplasmic reticulum, and RELB, a transcription factor that is associated with non-canonical NF-κB signaling. [ABSTRACT FROM AUTHOR]

Summary Therapeutic harnessing of adaptive immunity via checkpoint inhibition has transformed the treatment of many cancers. Despite unprecedented long-term responses, most patients do not respond to these therapies. Immunotherapy non-responders often harbor high levels of circulating myeloid-derived suppressor cells (MDSCs)—an immunosuppressive innate cell population. Through genetic and pharmacological approaches, we uncovered a pathway governing MDSC abundance in multiple cancer types. Therapeutic liver-X nuclear receptor (LXR) agonism reduced MDSC abundance in murine models and in patients treated in a first-in-human dose escalation phase 1 trial. MDSC depletion was associated with activation of cytotoxic T lymphocyte (CTL) responses in mice and patients. The LXR transcriptional target ApoE mediated these effects in mice, where LXR/ApoE activation therapy elicited robust anti-tumor responses and also enhanced T cell activation during various immune-based therapies. We implicate the LXR/ApoE axis in the regulation of innate immune suppression and as a target for enhancing the efficacy of cancer immunotherapy in patients. [ABSTRACT FROM AUTHOR]

The tumor microenvironment harbors a variety of different cell types that differentially impact tumor biology. In this issue of Cell Reports Methods, Raffo-Romero et al. standardized and optimized 3D tumor organoids to model the interactions between tumor-associated macrophages and tumor cells in vitro., Competing Interests: Declaration of interests The author declares no competing interests., (Copyright © 2024 The Author(s). Published by Elsevier Inc. All rights reserved.)

The secreted lipid transporter apolipoprotein E (APOE) plays important roles in atherosclerosis and Alzheimer's disease and has been implicated as a suppressor of melanoma progression. The APOE germline genotype predicts human melanoma outcomes, with APOE4 and APOE2 allele carriers exhibiting prolonged and reduced survival, respectively, relative to APOE3 homozygotes. While the APOE4 variant was recently shown to suppress melanoma progression by enhancing antitumor immunity, further work is needed to fully characterize the melanoma cell-intrinsic effects of APOE variants on cancer progression. Using a genetically engineered mouse model, we showed that human germline APOE genetic variants differentially modulate melanoma growth and metastasis in an APOE2>APOE3>APOE4 manner. The low-density lipoprotein receptor-related protein 1 (LRP1) receptor mediated the cell-intrinsic effects of APOE variants on melanoma progression. Protein synthesis was a tumor cell-intrinsic process differentially modulated by APOE variants, with APOE2 promoting translation via LRP1. These findings reveal a gain-of-function role for the APOE2 variant in melanoma progression, which may aid in predicting melanoma patient outcomes and understanding the protective effect of APOE2 in Alzheimer's disease., Significance: APOE germline variants impact melanoma progression through disparate mechanisms, such as the protein synthesis-promoting function of the APOE2 variant, indicating that germline genetic variants are causal contributors to metastatic outcomes., (©2023 American Association for Cancer Research.)

Cancer cells need to acquire specific molecular traits in order to spread to distant organs. In this issue of Developmental Cell, Marsh et al. show that autophagy restricts the outgrowth of breast cancer metastases in contrast to its impact on primary tumor progression., (Copyright © 2020 Elsevier Inc. All rights reserved.)

Targeted therapy of Philadelphia chromosome-positive chronic myeloid leukemia (CML) using the tyrosine kinase inhibitor imatinib mesylate has been one of the most striking achievements in modern cancer medicine. However, while imatinib can establish long-term remission in many cases, resistance to or intolerance of imatinib is eventually experienced by a substantial number of patients. Subsequent advances have led to the development of novel tyrosine kinase inhibitors (TKIs). One such inhibitor, nilotinib, was rationally designed to increase its affinity and specificity for the oncogenic tyrosine kinase Bcr-Abl compared with imatinib and has been shown to be effective after imatinib failure. Recently, nilotinib has been shown to be more effective when used as first-line therapy of chronic phase CML.