Obesity-induced changes to the immune landscape in human renal cell carcinoma subjects

Abstract

Immunotherapy for advanced renal cell carcinoma (RCC) has shown tremendous promise. However, clinical responses remain <30% and the reasons are unclear. Obesity affects ~35% of U.S. adults and is a major risk factor for RCC. We reported previously that obesity impairs immunotherapeutic efficacy in a murine renal cancer model, due to increased myeloid suppressor cells and weakened effector CD8 T cell responses. Based on these results, we hypothesized that obesity would also induce detrimental shifts in the immune landscape in treatment-naive subjects with confirmed RCC. In an IRB-approved study, we consented 86 RCC subjects with obesity (mean BMI = 38.4) and 77 normal to over-weight RCC subjects (mean BMI = 25.0), plus tumor-free controls, into a prospective study to examine intra-tumoral and systemic leukocytes by multi-parameter flow cytometry, plasma proteins via multiplex, and tumor gene expression by Nanostring. Numerous systemic cell populations (ex: CD45RO+ PD1+ CD4 or CD8 T cells, and HLA-DR- CD14− CD11b+MDSC, all p>0.05) were unaltered by obesity in RCC subjects. Peripheral CD14+ inflammatory monocytes and Foxp3+ Tregs were decreased in RCC subjects with obesity (both p< 0.05). However, obesity altered plasma proteins to favor RCC progression, with increased angiopoietin, VEGF-A and –C, and IL-8 (all p< 0.05). Within renal tumors, obesity did not alter CD4 or CD8 T cell percentages or phenotypes (CD45RO, PD1, CD56). Nanostring analysis of renal tumors revealed multiple obesity-related changes in pro-tumorigenic genes. Thus, obesity in RCC subjects had surprisingly few effects on cellular immunity, but multiple effects on protein mediators that may shift the overall immune landscape toward one that favors tumor progression.