Abstract B035: Leveraging therapy-induced senescence for prostate cancer immunotherapy
Authors: Zhou Lin , Murphy Katherine C. , Snyder Jarin , DeMarco Kelly D. , Ma Boyang , Ruscetti Marcus 
Published: June 2023

Abstract
Most prostate cancers are immunologically “cold” with poor tumor immunogenicity and a lack of cytotoxic T cells, and as such are generally unresponsive to immune checkpoint blockade (ICB) therapies that can reactivate T cell immunity and lead to durable and curative responses in other treatment-refractory solid tumors. We recently demonstrated that therapeutic induction of a durable growth arrest phenotype known as cellular senescence in the setting of pancreatic cancer can be novel approach to make “cold” tumors “hot” and sensitize them to anti-PD-1 ICB (Ruscetti et al. Cell 2020). This senescence-driven immunological effect is mediated through induction of immunomodulatory cell surface molecules, including MHC-I expression required for antigen presentation to T cells, and activation of the senescence-associated secretory phenotype (SASP), a collection of pleiotropic cytokines, chemokines, and other growth factors that can remodel the surrounding tumor-immune landscape. While this acute SASP activation can promote cytotoxic CD8+ T and Natural Killer (NK) cell anti-tumor immunity in some contexts, chronic SASP can alternatively lead to immune suppression and tumor cell invasion and metastasis that contributes to relapse after therapy. Here we set out to characterize the senescence-inducing capacity of chemotherapies, DNA repair inhibitors, and cell cycle targeting agents implicated in cellular senescence and used in the treatment of castration-resistant prostate cancer (CRPC), and the impact of their subsequent SASPs on immune responses and therapy outcomes. Using a suite of genetically-defined murine prostate cancer cell lines and an in vitro pipeline to rapidly define senescence phenotypes following treatment, we found that many commonly used cancer therapeutics can induce cellular senescence, with chemotherapies, Aurora kinase inhibitors, and CDK inhibitors producing the most robust senescence-induced cell cycle arrest across conditions. Prostate tumor cells harboring compound tumor suppressor losses such as Pten, p53, and Rb1 were more susceptible to therapeutic senescence induction. Strikingly, only a subset of therapies that induce senescence-associated growth arrest produced an inflammatory SASP and induction of activating NK cell ligands and antigen presentation and processing genes necessary for NK and T cell immunity. Moreover, whereas most SASPs induced NK cell activity in vitro, they also polarized macrophages toward a pro-tumorigenic and immune suppressive M2 phenotype that may limit their anti-tumor efficacy. CDK inhibitors produced a SASP that could activate lymphocytes without inducing suppressive myeloid populations in MYC-driven tumors, suggesting their use may be a promising approach to target prostate cancers harboring the currently “undruggable” MYC oncogene. Collectively, our studies demonstrate that induction of senescence and its non-cell autonomous arm, the SASP, could be a unique approach to treat CRPC and create new immunological dependencies that can be potentially harnessed for prostate cancer immunotherapy.
Citation Format: Lin Zhou, Katherine C. Murphy, Jarin Snyder, Kelly D. DeMarco, Boyang Ma, Marcus Ruscetti. Leveraging therapy-induced senescence for prostate cancer immunotherapy [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr B035.