Obesity diminishes response to PD-1-based immunotherapies in renal cancer

Abstract

BackgroundObesity is a major risk factor for renal cancer, yet our understanding of its effects on antitumor immunity and immunotherapy outcomes remains incomplete. Deciphering these associations is critical, given the growing clinical use of immune checkpoint inhibitors for metastatic disease and mounting evidence for an obesity paradox in the context of cancer immunotherapies, wherein obese patients with cancer have improved outcomes.MethodsWe investigated associations between host obesity and anti-programmed cell death (PD-1)-based outcomes in both renal cell carcinoma (RCC) subjects and orthotopic murine renal tumors. Overall survival (OS) and progression-free survival (PFS) were determined for advanced RCC subjects receiving standard of care anti-PD-1 who had ≥6 months of follow-up from treatment initiation (n=73). Renal tumor tissues were collected from treatment-naive subjects categorized as obese (body mass index, ‘BMI’ ≥30 kg/m2) or non-obese (BMI <30 kg/m2) undergoing partial or full nephrectomy (n=19) then used to evaluate the frequency and phenotype of intratumoral CD8+ T cells, including PD-1 status, by flow cytometry. In mice, antitumor immunity and excised renal tumor weights were evaluated ±administration of a combinatorial anti-PD-1 therapy. For a subset of murine renal tumors, immunophenotyping was performed by flow cytometry and immunogenetic profiles were evaluated via nanoString.ResultsWith obesity, RCC patients receiving anti-PD-1 administration exhibited shorter PFS (p=0.0448) and OS (p=0.0288). Treatment-naive renal cancer subjects had decreased frequencies of tumor-infiltrating PD-1highCD8+ T cells, a finding recapitulated in our murine model. Following anti-PD-1-based immunotherapy, both lean and obese mice possessed distinct populations of treatment responders versus non-responders; however, obesity reduced the frequency of treatment responders (73% lean vs 44% obese). Tumors from lean and obese treatment responders displayed similar immunogenetic profiles, robust infiltration by PD-1int interferon (IFN)γ+CD8+ T cells and reduced myeloid-derived suppressor cells (MDSC), yielding favorable CD44+CD8+ T cell to MDSC ratios. Neutralizing interleukin (IL)-1β in obese mice improved treatment response rates to 58% and reduced MDSC accumulation in tumors.ConclusionsWe find that obesity is associated with diminished efficacy of anti-PD-1-based therapies in renal cancer, due in part to increased inflammatory IL-1β levels, highlighting the need for continued study of this critical issue.

Diet-Induced Obesity Impairs Outcomes and Induces Multi-Factorial Deficiencies in Effector T Cell Responses Following Anti-CTLA-4 Combinatorial Immunotherapy in Renal Tumor-Bearing Mice

“…Subgroup analysis within a recent meta-analysis showed that RCC patients with a high BMI undergoing ICB tended to experience worse outcomes (HR = 1.10, CI: 0.50–2.41, p = 0.810) [ 27 ]. This trend is supported by our recent analysis of outcomes in RCC patients following ICB administration, wherein patients with obesity had worse progression-free survival and overall survival [ 9 ]. In contrast, Sanchez et al [ 28 ] found no significant association between obesity and ICB outcomes in RCC but these authors did identify a strong trend toward beneficial effects of obesity.…”

“…Mounting evidence indicates that obesity negatively impacts immune function and immune-based interventions, with multiple laboratories, including our own, reporting that increased adiposity blunts anti-tumor immunity and increases tumor growth in multiple preclinical models [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. Previously, we determined that DIO was associated with increased intratumoral frequencies of immunosuppressive dendritic cells (DC) [ 3 ] and myeloid-derived suppressor cells (MDSCs) [ 4 ] and a reduced efficacy of AdT/CpG in Renca tumor-bearing mice [ 3 ].…”

“…Obesity increases the risk of developing thirteen different types of cancers, including renal cell carcinoma (RCC) [ 2 ]. Obesity can negatively impact immune function and has been shown to blunt anti-tumor immunity and promote accelerated tumor growth in multiple preclinical models [ 3 , 4 , 5 , 6 , 7 , 8 , 9 , 10 , 11 , 12 ]. However, obesity-induced alterations in systemic inflammation, signaling factors, and metabolites may have both beneficial and detrimental effects on T cell anti-tumor immunity [ 13 ].…”

“…A separate study by Sanchez et al [ 28 ] found no significant association between obesity and ICB outcomes in RCC, although their data trended toward obesity being favorable. More recently, we found that RCC patients with obesity at treatment initiation had worse outcomes following anti (α)-Programmed Cell Death-1 (αPD-1) therapy [ 9 ]. With the increased use of combinatorial ICB therapies as standard of care for patients with advanced RCC, additional studies are needed to further elucidate these complex relationships and identify the mechanisms that shape outcomes.…”

Clinical Features and Multiplatform Molecular Analysis Assist in Understanding Patient Response to Anti-PD-1/PD-L1 in Renal Cell Carcinoma

“…Results of standard clinical tests on peripheral blood, including elevated absolute lymphocyte count (ALC) [12], or lower absolute neutrophil count (ANC) [12,13], neutrophil-to-lymphocyte ratio (NLR) [12][13][14][15], and monocyte-to-lymphocyte ratio (MLR) [14], have been associated with better response in solid tumors but not prospectively validated. In addition, the relationship between body mass index (BMI) and response is still disputable, with studies demonstrating improved response and survival in RCC patients with higher BMI [16,17] and others showing the opposite [18].…”