Overcoming obesity-induced immunotherapeutic failure

Obesity is a leading public health concern that affects u003e37% of US adults and increases the risk of developing 13 types of cancer, including renal cancer. Renal cancer is treated by immunotherapy, but the impact of obesity on immunotherapy efficacy remains unclear. We addressed this issue by evaluating treatment efficacy in lean or diet-induced obese (DIO) mice with orthotopic renal tumors. Endogenous T cell priming with adenovirus-encoded TRAIL + CpG (AdTR/CpG) significantly reduced renal tumors in lean mice, but failed in ~80% of DIO mice. We then asked: 1) if failure were specific to this model and 2) if it could be reversed by reinvigoration of T cells with checkpoint blockade. Here, we report that obesity-induced impairment occurs across multiple immunotherapies and tumor types, and is independent of diet alone. Combining AdTR/CpG with checkpoint blockade (either anti-PD-1 or anti-CTLA-4) improved response rates in DIO mice with renal tumors to 44% and 67%, respectively. nanoString immunogenetic profiling of responder versus non-responder tumors revealed increases in T cell-related genes with concomitant decreases in myeloid/dendritic cell genes in responder mice (coined a ‘T cell-myeloid-inversion (TMI) signature’). These results were supported by flow cytometric data, which revealed increased intratumoral CD8+ T cell : Treg ratios and decreased myeloid-derived suppressor cells and tolerogenic dendritic cells in responders. Our results identify obesity as a confounder of immunotherapeutic efficacy that can be partially overcome by combining upstream T cell priming agents with checkpoint blockade. Further investigations will be aimed at targeting immunosuppressive populations to further boost therapeutic efficacy.