Uncovering the heterogenous role of senescence in prostate immune suppression and tumorigenesis

PROJECT SUMMARY Prostate cancer is the second-leading cause of cancer-related death in American men. While most prostate cancers are hormone sensitive and respond well to hormone therapy, a subset of patients will relapse with lethal castration-resistant prostate cancer. It is still unclear why some prostate tumors remain indolent yet others rapidly progress and relapse on therapy. As such there is an urgent need for new biomarkers of disease progression and novel therapeutic targets and strategies for treatment-refractory prostate cancer. We and others have identified markers of cellular senescence, a stress-induced program driven by oncogenic insult, in prostate cancers from genetically engineered mouse models (GEMMs) and human patients. As senescence leads to durable cell cycle arrest and induction of a senescence-associated secretory phenotype (SASP) that can activate immune clearance of senescent cells, it has historically been thought that senescence may act as a natural barrier to tumorigenesis. However, more recent evidence has demonstrated that chronic senescence and SASP production can alternatively lead to systemic inflammation that sets the stage of tumor development and subsequent progression and metastasis. Whether senescence or specific senescent cell types functionally contribute to prostate cancer onset, progression, and immune suppression remains unknown. To address this question, we have crossed GEMMs we have developed that recapitulate the early and late stages of prostate tumorigenesis with p16-3MR mice that allow tracking and depletion of p16+ senescent cells. Using these models and prostate cancer patient samples we observed that markers of cellular senescence remain elevated during disease progression and can be found in multiple heterogenous cell types, and that depletion of senescent cells can block tumor formation and reverse immune suppression. As such we hypothesize that senescent cells promote prostate immune suppression and tumorigenesis and their targeting can reactivate immune-mediated tumor control. In Aim 1, we will use multiplexed staining, single cell spatial transcriptomics, and ex vivo functional analyzes to identify and phenotypically characterize distinct populations of senescent cells during disease progression in prostate cancer GEMMs and patient samples. In Aim 2, genetic and pharmacological tools will be used to assess the impact of senescent cell depletion (i.e. senolysis) and SASP suppression on tumor progression. In Aim 3, we will evaluate whether senolytic therapy can reverse prostate immune suppression and potentiate currently ineffective anti-PD-1 immune checkpoint blockade (ICB) therapy to drive immune-mediated prostate cancer control in the preclinical setting. Collectively, these approaches have the potential to not only advance our basic mechanistic understanding of how senescence- mediated inflammation can foster tumorigenesis, but also guide the translational development of (a) prognostic biomarkers of aggressive disease and (b) new therapeutic targets and strategies for treating prostate cancer.