Journal article
Obesity diminishes response to PD-1-based immunotherapies in renal cancer
Journal for immunotherapy of cancer, Vol.8(2), e000725
12/2020
DOI: 10.1136/jitc-2020-000725
PMCID: PMC7757487
PMID: 33427691
Abstract
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.
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/m
) or non-obese (BMI <30 kg/m
) 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.
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
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
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.
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.
Details
- Title: Subtitle
- Obesity diminishes response to PD-1-based immunotherapies in renal cancer
- Creators
- Shannon K Boi - Graduate Biomedical Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USARachael M Orlandella - Graduate Biomedical Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USAJustin Tyler Gibson - Graduate Biomedical Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USAWilliam James Turbitt - Department of Nutrition Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USAGal Wald - Department of Urology, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USALewis Thomas - Department of Urology, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USAClaire Buchta Rosean - Department of Urology, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USAKatlyn E Norris - Honors Undergraduate Research Program, School of Health Professions, The University of Alabama at Birmingham, Birmingham, Alabama, USAMegan Bing - Department of Urology, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USALaura Bertrand - Department of Urology, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USABrett P Gross - Interdisciplinary Program in Immunology, The University of Iowa, Iowa City, Iowa, USAAmani Makkouk - Interdisciplinary Program in Immunology, The University of Iowa, Iowa City, Iowa, USADmytro Starenki - HudsonAlpha Institute for Biotechnology, Huntsville, Alabama, USAKristine I Farag - Science and Technology Honors Program, College of Arts and Sciences, The University of Alabama at Birmingham, Birmingham, Alabama, USARobert E Sorge - Department of Psychology, The University of Alabama at Birmingham, Birmingham, Alabama, USAJames A Brown - University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa, USAJennifer Gordetsky - Departments of Pathology and Urology, Vanderbilt University Medical Center, Nashville, Tennessee, USAHesham Yasin - Department of Internal Medicine, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USARohan Garje - Genitourinary Oncology Program, Division of Hematology, Oncology and Blood and Marrow Transplantation, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USALakshminarayanan Nandagopal - The University of Alabama at Birmingham O'Neal Comprehensive Cancer Center, Birmingham, Alabama, USAGeorge J Weiner - Department of Internal Medicine, Division of General Medicine, University of Iowa Roy J and Lucille A Carver College of Medicine, Iowa City, Iowa, USADavid M Lubaroff - University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa, USARebecca C Arend - Department of Obstetrics and Gynecology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USAPeng Li - Department of Biostatistics, The University of Alabama at Birmingham School of Nursing, Birmingham, Alabama, USAYousef Zakharia - Genitourinary Oncology Program, Division of Hematology, Oncology and Blood and Marrow Transplantation, The University of Iowa, Iowa City, Iowa, USAEddy Yang - Department of Radiation Oncology, The University of Alabama at Birmingham School of Medicine, Birmingham, Alabama, USAAliasger K Salem - Division of Pharmaceutics and Translational Therapeutics, University of Iowa College of Pharmacy, Iowa City, Iowa, USAKenneth Nepple - University of Iowa Holden Comprehensive Cancer Center, Iowa City, Iowa, USATatiana T Marquez-Lago - Department of Cell, Developmental and Integrative Biology, The University of Alabama at Birmingham, Birmingham, Alabama, USALyse A Norian - The University of Alabama at Birmingham O'Neal Comprehensive Cancer Center, Birmingham, Alabama, USA
- Resource Type
- Journal article
- Publication Details
- Journal for immunotherapy of cancer, Vol.8(2), e000725
- DOI
- 10.1136/jitc-2020-000725
- PMID
- 33427691
- PMCID
- PMC7757487
- NLM abbreviation
- J Immunother Cancer
- eISSN
- 2051-1426
- Grant note
- T32 GM008111 / NIGMS NIH HHS P30 DK079626 / NIDDK NIH HHS T32 DK062710 / NIDDK NIH HHS R25 CA047888 / NCI NIH HHS S10 OD021697 / NIH HHS T32 CA183926 / NCI NIH HHS R01 CA181088 / NCI NIH HHS T32 HL105349 / NHLBI NIH HHS T32 AI007051 / NIAID NIH HHS P30 CA086862 / NCI NIH HHS P30 CA013148 / NCI NIH HHS P30 DK056336 / NIDDK NIH HHS
- Language
- English
- Date published
- 12/2020
- Academic Unit
- Roy J. Carver Department of Biomedical Engineering; Hematology, Oncology, and Blood & Marrow Transplantation; Pharmaceutical Sciences and Experimental Therapeutics; Craniofacial Anomalies Research Center; Urology; Dental Research; Chemical and Biochemical Engineering; General Internal Medicine; Internal Medicine
- Record Identifier
- 9984216583802771
Metrics
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