TY - JOUR
T1 - Obesity diminishes response to PD-1-based immunotherapies in renal cancer
AU - Boi, Shannon K.
AU - Orlandella, Rachael M.
AU - Gibson, Justin Tyler
AU - Turbitt, William James
AU - Wald, Gal
AU - Thomas, Lewis
AU - Buchta Rosean, Claire
AU - Norris, Katlyn E.
AU - Bing, Megan
AU - Bertrand, Laura
AU - Gross, Brett P.
AU - Makkouk, Amani
AU - Starenki, Dmytro
AU - Farag, Kristine I.
AU - Sorge, Robert E.
AU - Brown, James A.
AU - Gordetsky, Jennifer
AU - Yasin, Hesham
AU - Garje, Rohan
AU - Nandagopal, Lakshminarayanan
AU - Weiner, George J.
AU - Lubaroff, David M.
AU - Arend, Rebecca C.
AU - Li, Peng
AU - Zakharia, Yousef
AU - Yang, Eddy
AU - Salem, Aliasger K.
AU - Nepple, Kenneth
AU - Marquez-Lago, Tatiana T.
AU - Norian, Lyse A.
N1 - Publisher Copyright:
© 2020 Author(s). Published by BMJ.
PY - 2020/12/22
Y1 - 2020/12/22
N2 - 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-1 high CD8 + 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-1 int interferon (IFN)3 + 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.
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-1 high CD8 + 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-1 int interferon (IFN)3 + 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.
KW - CD8-positive T-lymphocytes
KW - immunotherapy
KW - kidney neoplasms
KW - lymphocytes
KW - programmed cell death 1 receptor
KW - tumor-infiltrating
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U2 - 10.1136/jitc-2020-000725
DO - 10.1136/jitc-2020-000725
M3 - Article
C2 - 33427691
AN - SCOPUS:85098115696
SN - 2051-1426
VL - 8
JO - Journal for ImmunoTherapy of Cancer
JF - Journal for ImmunoTherapy of Cancer
IS - 2
M1 - e000725
ER -