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.
Understanding the effects of obesity on the immune profile of renal cell carcinoma (RCC) patients is critical, given the rising use of immunotherapies to treat advanced disease and recent reports of differential cancer immunotherapy outcomes with obesity. Here, we evaluated multiple immune parameters at the genetic, soluble protein, and cellular levels in peripheral blood and renal tumors from treatment-naive clear cell RCC (ccRCC) subjects (n = 69), to better understand the effects of host obesity (Body Mass Index "BMI" � 30 kg/ m 2 ) in the absence of immunotherapy. Tumor-free donors (n = 38) with or without obesity were used as controls. In our ccRCC cohort, increasing BMI was associated with decreased percentages of circulating activated PD-1 + CD8 + T cells, CD14 + CD16 neg classical monocytes, and Foxp3 + regulatory T cells (Tregs). Only CD14 + CD16 neg classical monocytes and Tregs were reduced when obesity was examined as a categorical variable. Obesity did not alter the percentages of circulating IFNγ + CD8 T cells or IFNγ + , IL-4 + , or IL-17A + CD4 T cells in ccRCC subjects. Of 38 plasma proteins analyzed, six (CCL3, IL-1β, IL-1RA, IL-10, IL-17, and TNFα) were upregulated specifically in ccRCC subjects with obesity versus tumor-free controls with obesity. IGFBP-1 was uniquely decreased in ccRCC subjects with obesity versus non-obese ccRCC subjects. Immunogenetic profiling of ccRCC tumors revealed that 93% of examined genes were equivalently expressed and no changes in cell type scores were found in stage-matched tumors from obesity category II/III versus normal weight (BMI � 35 kg/m 2 versus 18.5-24.9 kg/m 2 , respectively) subjects.
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.
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