Senolytic approaches enhance chemotherapy immunogenicity in prostate cancer
Cellular senescence is a common outcome of many standard-of-care cytostatic and cytotoxic cancer therapies. Whereas is some contexts therapy-induced senescence can drive tumor growth suppression and anti-tumor immune surveillance through the senescence-associated secretory phenotype (SASP), in others it can promote tumor progression, metastatic dissemination, and immune suppression. How the heterogeneous senescent phenotypes induced by different classes of cancer therapies directly impact tumor and immune responses, and whether understanding those mechanisms could be leveraged for effective combination therapies, has yet to be evaluated in a systematic manner. Here we compared the effects of various CDK inhibitor combinations, chemotherapies, and other DNA damaging agents commonly used in the treatment of advanced prostate cancer on senescence phenotypes in human and mouse prostate tumor models. We observed that while CDK inhibitors could induce senescence in MYC-driven prostate tumor cells, DNA-damaging chemotherapies and Aurora kinase inhibitors mediated a more robust senescence-mediated growth arrest and SASP program, which was paradoxically enhanced in the context of p53 and Rb tumor suppressor losses. The SASP produced by chemotherapy-induced senescence, and in particular with docetaxel, contained not only inflammatory factors that could influence innate immune responses, but also ECM remodeling factors that could facilitate tumor cell dissemination. Though docetaxel treatment could induce senescence and reduce tumor growth in syngeneic prostate cancer mouse models, it was not sufficient to activate anti-tumor immune surveillance or prevent metastatic dissemination. Use of senolytic therapies targeting anti-apoptotic BCL2 and IAP pathways upregulated after docetaxel-induced senescence could effectively clear senescent tumor cells. SMAC mimetic LCL-161 also induced immunogenic cell death capable to remodeling the inflammatory SASP to confer CD8+ T cell activation to further reduce tumor growth and even prevent metastasis in vivo. Our results suggest that combining senescence-inducing chemotherapies with senolytic agents can enhance the immunogenicity and anti-metastatic potential of standard-of-care chemotherapy used for treating prostate cancer patients. Overall design: Myc-CaP murine prostate tumor cells were treated for 6 days continously with different senescence-inducing therapies. Bulk RNA-seq analysis was then performed in triplicate.