MYC and p53 Alterations Cooperate through VEGF Signaling to Repress Cytotoxic T Cell and Immunotherapy Responses in Prostate Cancer

Abstract Patients with castration-resistant prostate cancer (CRPC) are generally unresponsive to tumor targeted treatments and immunotherapies. Genetic alterations acquired during the evolution of CRPC may impact anti-tumor immunity and immunotherapy responses, which could inform personalized therapeutic strategies. Using our innovative electroporation-based mouse models, we generated distinct genetic subtypes of CRPC found in patients and uncovered unique immune microenvironments. Specifically, mouse and human prostate tumors with MYC amplification and p53 disruption had weak cytotoxic lymphocyte infiltration and an overall dismal prognosis. MYC and p53 cooperated to induce tumor intrinsic secretion of VEGF, which signaled through VEGFR2 expressed on CD8+ T cells to directly inhibit T cell migration and effector functions. Targeting VEGF-VEGFR2 signaling in vivo remodeled the immune suppressive prostate tumor microenvironment, leading to CD8+ T cell-mediated primary tumor and metastasis growth suppression and significantly increased overall survival in MYC and p53 altered CPRC. VEGFR2 blockade also led to induction of PD-L1 in tumors and produced anti-tumor efficacy in combination with PD-L1 immune checkpoint blockade in multiple preclinical CRPC mouse models. Thus, these results identify a genetic mechanism of immune suppression through VEGF signaling in prostate cancer that can be targeted to reactivate immune and immunotherapy responses in an aggressive subtype of CRPC.