High dimensional analyses reveal IL-15 enhances activation of Sipuleucel-T lymphocyte subsets and reverses immunoresistance.

Sipuleucel-T (sip-T) is the only FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report high-dimensional analyses of sip-T using cytometry by time of flight (CyTOF) and show a lymphoid predominance, with CD3+ T cells constituting the highest proportion (median ~60%) of sip-T, followed by B cells, and natural killer (NK) and NKT cells. We hypothesized that treatment of sip-T with homeostatic cytokines known to activate/expand effector lymphocytes could augment efficacy against prostate tumors. Of the cytokines tested, IL-15 was the most effective at enhancing activation and proliferation of effector lymphocytes, as well as augmenting tumor cytotoxicity in vitro. Co-culture of sip-T with IL-15 and control or prostate-relevant antigens showed substantial activation and expansion of CD8+ T cells and NKT cells in an antigen-specific manner. Adoptive transfer of IL-15-treated sip-T into NSG mice resulted in more potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2-14-fold higher influx of sip-T and a significant increase in IFN-γ producing CD8+ T cells and NKT cells within the tumor microenvironment (TME) in the IL-15 group. In conclusion, we put forward evidence that IL-15 treatment can enhance the functional antitumor immunity of sip-T, providing rationale for combining IL-15 or IL-15 agonists with sip-T to treat patients with mCRPC.