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Systematic identification of tumor-intrinsic resistance mechanisms and combinatorial therapy targets for immunotherapy

ABSTRACT: A number of reports have demonstrated that tumor-intrinsic mechanisms of resistance, such as the loss of genes critical for antigen presentation and inflammatory responses, along with the activation of various cellular signaling cascades, can limit the efficacy of immunotherapy. Strategies to sensitize tumor cells to immunotherapy may overcome some resistance mechanisms, but identifying therapeutic targets has remained challenging. Here, we integrate a two-cell type (2CT) whole-genome CRISPR-Cas9 screen with dynamic transcriptional profiling of the tumor/T cell interaction to comprehensively identify tumor genes that are induced to promote tumor survival. We assessed the therapeutic potential of pharmacological inhibition of these and other top CRISPR identified targets as combinatorial targets to improve the efficacy of tumor destruction by T cells.

ORGANISM(S): Homo sapiens

PROVIDER: GSE137824 | GEO | 2022/08/31

REPOSITORIES: GEO

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Project description:Prostate cancer is the second leading cause of cancer-related death among American men. Prostate tumor cells exhibit significant tropism for the bone and once metastasis occurs, survival rates fall significantly. Current treatment options are not curative and focus on symptom management. Immunotherapies are rapidly emerging as a possible therapeutic option for a variety of cancers including prostate cancer, however, variable patient response remains a concern. Chemotherapies, like cabozantinib, can have immune-priming effects which sensitize tumors to immunotherapies. Additionally, lower doses of chemotherapy can be used in this context which can reduce patient side effects. We hypothesized that a combination of chemotherapy (cabozantinib) and immunotherapy (Interleukin-27 (IL-27)) could be used to treat bone-metastatic prostate cancer and exert pro-osteogenic effects. IL-27 is a multi-functional cytokine, which promotes immune cell recruitment to tumors, while also promoting bone repair. To test this hypothesis, in vivo experiments were performed where syngeneic C57BL/6J mice were implanted intratibially with TRAMP-C2ras-Luc cells that are able to form tumors in bone. Immunotherapy was administered in the form of intramuscular gene therapy, delivering plasmid DNA encoding a reporter gene (Lucia), and/or a therapeutic gene (IL-27). Sonoporation was used to aid gene delivery. Following immunotherapy, the animals received either cabozantinib or a vehicle control by oral gavage. Bioluminescence imaging was used to monitor tumor size over time. Combinatorial therapy inhibited tumor growth and improved survival. Further, RNA sequencing was used to investigate the mechanisms involved. Microcomputed tomography and differentiation assays indicated that the combination therapy improved bone quality by enhancing osteoblast differentiation and inhibiting osteoclast differentiation. Our conclusion is that a chemo-immunotherapy approach such as the one examined in this work has potential to emerge as a novel therapeutic strategy for treating bone-metastatic prostate cancer. This approach will enable a significant reduction in chemotherapy-associated toxicity, enhance sensitivity to immunotherapy, and improve bone quality.

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Systematic identification of tumor-intrinsic resistance mechanisms and combinatorial therapy targets for immunotherapy

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