High dimensional analyses reveal activation of lymphocyte subsets and reversal of immunoresistance by cytokine enhancement of adoptive cellular vaccine therapy in prostate cancer.

Engineered cell therapies have emerged as a potent therapeutic option for the hematologic malignancies, however solid tumor responses to similar approaches have been modest. The outlier is Sipuleucel-T (sip-T), an FDA-approved autologous cellular immunotherapy for metastatic castration-resistant prostate cancer (mCRPC). To elucidate parameters of the response profile to this therapy, we report the first high dimensional cellular analyses of sip-T using mass cytometry (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 cancer. Of cytokines tested, IL-15 treated sip-T showed the most significant activation and proliferation of effector lymphocytes, as well as augmentation of tumor cytotoxicity in vitro. Co-culture of sip-T with IL-15 and control or prostate-relevant antigens showed significant activation and expansion of CD8 T and NKT cells in an antigen-specific manner. Adoptive transfer of IL-15 treated sip-T into NSG mice resulted in potent prostate tumor growth inhibition compared with control sip-T. Evaluation of tumor-infiltrating lymphocytes revealed a 2 to 14-fold higher influx of sip-T and a significant increase in interferon (IFN)-{gamma} producing CD8+ T and NKT cells within the tumor microenvironment (TME) in the IL-15 group. In conclusion, we put forward the first evidence that IL-15 treatment can enhance the functional anti-tumor efficacy of sip-T, providing rationale for combining IL-15 or IL-15 agonists with sip-T to treat mCRPC patients. Graphical Abstract O_FIG O_LINKSMALLFIG WIDTH=200 HEIGHT=138 SRC="FIGDIR/small/550213v1_ufig1.gif" ALT="Figure 1"> View larger version (34K): org.highwire.dtl.DTLVardef@130adb0org.highwire.dtl.DTLVardef@db2567org.highwire.dtl.DTLVardef@174a953org.highwire.dtl.DTLVardef@18c049_HPS_FORMAT_FIGEXP M_FIG C_FIG One sentence summaryIL-15 treatment can enhance the efficacy/anti-tumor immunity of sipuleucel-T by modulating CD8+ T-cell and CD56+ NKT subsets.