Enhanced anti-tumor effects of the PD-1 blockade combined with a highly absorptive form of curcumin targeting STAT3

Abstract

PD-1/PD-L1 immune checkpoint inhibitors are promising cancer immunotherapies however responses are still limited and the development of more effective combination immunotherapy is needed. We previously reported that STAT3 activation in cancer cells and immune cells was involved in immune-resistant mechanisms. In this study, we evaluated the effect of highly absorptive forms of curcumin extracts and synthetic curcumin on anti-tumor T cell responses. The curcumin po administration resulted in the significant augmentation of in vivo induction of tumor antigen-specific T cells through restoration of dendritic cells (DCs) by inhibiting directly STAT3 in DCs and indirectly via reduced IL-6 production from STAT3 activated cancer cells in 2 syngeneic MC38 and CT26 murine tumor models. Curcumin also showed direct DC enhancing activity and enhanced T cell induction for the immunized antigens in non-tumor-bearing mice and human hosts. Curcumin restored DC functions in xenogeneic nude mouse model implanted with high IL-6-producing human clear cell ovarian cancer cells. The combination of curcumin and PD-1/PD-L1 Abs demonstrated a synergistic anti-tumor activity in MC38 murine tumor models. These results indicated that curcumin augments the induction of tumor antigen-specific T cells by restoring the T cell stimulatory activity of DCs targeting activated STAT3 in both cancer cells and immune cells. Combination immunotherapy with curcumin and PD-1/PD-L1 Ab is an attractive strategy in the development of effective immunotherapy against various cancers.

Keywords: PD-1/PD-L1 blockade; STAT3; cancer immunotherapy; curcumin; dendritic cells.