RT Journal Article SR Electronic T1 Obesity diminishes response to PD-1-based immunotherapies in renal cancer JF Journal for ImmunoTherapy of Cancer JO J Immunother Cancer FD BMJ Publishing Group Ltd SP e000725 DO 10.1136/jitc-2020-000725 VO 8 IS 2 A1 Shannon K Boi A1 Rachael M Orlandella A1 Justin Tyler Gibson A1 William James Turbitt A1 Gal Wald A1 Lewis Thomas A1 Claire Buchta Rosean A1 Katlyn E Norris A1 Megan Bing A1 Laura Bertrand A1 Brett P Gross A1 Amani Makkouk A1 Dmytro Starenki A1 Kristine I Farag A1 Robert E Sorge A1 James A Brown A1 Jennifer Gordetsky A1 Hesham Yasin A1 Rohan Garje A1 Lakshminarayanan Nandagopal A1 George J Weiner A1 David M Lubaroff A1 Rebecca C Arend A1 Peng Li A1 Yousef Zakharia A1 Eddy Yang A1 Aliasger K Salem A1 Kenneth Nepple A1 Tatiana T Marquez-Lago A1 Lyse A Norian YR 2020 UL http://jitc.bmj.com/content/8/2/e000725.abstract AB Background Obesity 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.Methods We 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.Results With 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.Conclusions We 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.