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MYC and p53 cooperate through VEGF signaling to repress cytotoxic T cell and immunotherapy responses in prostate cancer

ABSTRACT: To study the genetic factors that influence the immune landscape of castration-resistant prostate cancer (CRPC), we utilized a flexible, electroporation-based system to introduce genetic alterations relevant to human disease directly into the prostate glands of mice. These electroporation-based genetically engineered mouse models (EPO-GEMM) recapitulate features of traditional models, and allow us to investigate distinct genetic subtypes of prostate cancer within an intact tumor-immune microenvironment. We observed differences between genetic subtypes of CRPC, with MYC-driven subtypes exhibiting a "cold" immune landscape compared to others. Interestingly, we found that the compound loss of different tumor suppressors such as Pten or p53 with MYC further impacts the inflammatory profile of prostate cancer, with MYC and p53 (MP) alterations cooperating to drive VEGF expression and immune suppression. VEGF signaling blockade resulted in re-activation of cytotoxic T cell anti-tumor immunity and restored sensitivity to immunotherapy in MP CRPC. Thus, by leveraging the power of EPO-GEMMs to generate distinct subtypes of CRPC, our studies reveal a functional role for VEGF signaling in driving prostate cancer immune evasion and validate the VEGF pathway as an actionable therapeutic target in MYC and p53 altered prostate cancer.

ORGANISM(S): Mus musculus

PROVIDER: GSE271975 | GEO | 2024/08/26

REPOSITORIES: GEO

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