Robust antigen-specific CD8 T cell tolerance to a model prostate cancer neoantigen

Immunotherapy has shown limited success in prostate cancer; this may be partially explained by its immunosuppressive tumor microenvironment (TME). Although androgen-deprivation therapy (ADT), the most common treatment for prostate cancer, initially promotes a robust T cell infiltrate, T cell responses are later attenuated. Based on the castration-sensitive Myc-CaP model, we developed an antigen-specific system to study CD8 T cell tolerance to prostate tumors. This model is unique in that CD8 T cells recognize a bona-fide tumor antigen (Her-2/neu), rather than an overexpressed xenogenic antigen like chicken ovalbumin or influenza hemagglutinin. Using this novel model, we demonstrate robust tolerance that is not alleviated by TLR agonists or ADT. This model may serve as a novel and useful tool to further interrogate methods by which to augment anti-tumor cancer immune responses to prostate cancer. Significance Prostate cancer is a leading cause of cancer-related death in men worldwide, with an estimated 33,000 deaths projected in the U.S. in 2020. Although primary (localized) tumors can be cured by surgery or radiation, approximately 40% of patients eventually develop recurrent disease. While initially responsive to androgen-deprivation, many patients with recurrent prostate cancer eventually progress to a more advanced disease state known as metastatic castration-resistant prostate cancer (mCRPC); this is the lethal phenotype. These studies describe a novel androgen-responsive murine cell line that expresses a bona-fide tumor antigen (Her-2/neu). Pre-clinical work with this model shows robust and antigen-specific CD8 T cell tolerance, providing a novel preclinical model to study CD8 T cell tolerance to prostate tumors

Castration-mediated IL-8 promotes myeloid infiltration and prostate cancer progression

Unlike several other tumor types, prostate cancer (PCa) rarely responds to immune checkpoint blockade (ICB). To define tumor-cell intrinsic factors that contribute to PCa progression and resistance to ICB, we analyzed PCa epithelial cells from castration-sensitive and castration-resistant samples using implanted tumors, cell lines, transgenic models, and human tissue. We found that castration resulted in increased expression of Interleukin-8 (IL-8) and its likely murine homolog Cxcl15 in prostate epithelial cells. We showed that these chemokines drove subsequent intra-tumoral infiltration of tumor-promoting polymorphonuclear myeloid-derived suppressor cells (PMN-MDSCs), which was largely abrogated when IL-8 signaling was blocked genetically or pharmacologically. Targeting IL-8 signaling in combination with ICB delayed the onset of castration-resistance and increased the density of polyfunctional CD8 T cells in tumors. Our findings establish a novel mechanism by which castration mediates IL-8 secretion and subsequent PMN-MDSC infiltration and highlight blockade of the IL8/CXCR2 axis as a potential therapeutic intervention