Key Points
Obesity enhances tumor growth while priming macrophages for inflammatory phenotypes.
The obesity-associated hormone leptin is sufficient to enhance antitumor immunity.
Leptin reprograms macrophages to complement PD-1 blockade immunotherapy.
Abstract
Although obesity can promote cancer, it may also increase immunotherapy efficacy in what has been termed the obesity-immunotherapy paradox. Mechanisms of this effect are unclear, although obesity alters key inflammatory cytokines and can promote an inflammatory state that may modify tumor-infiltrating lymphocytes and tumor-associated macrophage populations. To identify mechanisms by which obesity affects antitumor immunity, we examined changes in cell populations and the role of the proinflammatory adipokine leptin in immunotherapy. Single-cell RNAseq demonstrated that obesity decreased tumor-infiltrating lymphocyte frequencies, and flow cytometry confirmed altered macrophage phenotypes with lower expression of inducible NO synthase and MHC class II in tumors of obese animals. When treated with anti-programmed cell death protein 1 (PD-1) Abs, however, obese mice had a greater absolute decrease in tumor burden than lean mice and a repolarization of the macrophages to inflammatory M1-like phenotypes. Mechanistically, leptin is a proinflammatory adipokine that is induced in obesity and may mediate enhanced antitumor immunity in obesity. To directly test the effect of leptin on tumor growth and antitumor immunity, we treated lean mice with leptin and observed tumors over time. Treatment with leptin, acute or chronic, was sufficient to enhance antitumor efficacy similar to anti-PD-1 checkpoint therapy. Further, leptin and anti-PD-1 cotreatment may enhance antitumor effects consistent with an increase in M1-like tumor-associated macrophage frequency compared with non–leptin-treated mice. These data demonstrate that obesity has dual effects in cancer through promotion of tumor growth while simultaneously enhancing antitumor immunity through leptin-mediated macrophage reprogramming.
Footnotes
This work was supported by U.S. Department of Health and Human Services (HHS), National Institutes of Health (NIH), National Cancer Institute (NCI) Grants F30 CA224559 (S.O.D.), K00 CA234920 (J.E.B.), F30 CA239367 (M.Z.M.), F30 CA247202 (B.I.R.), and R01 CA217987 (J.C.R.); HHS, NIH, National Institute of General Medical Sciences Grant T32 GM007347 (S.O.D., M.Z.M., B.I.R., and A.A.); and HHS, NIH, National Institute of Diabetes and Digestive and Kidney Diseases Grants T32 DK101003 (S.O.D.) and R01 DK106090 (N.J.M.). The Vanderbilt VANTAGE Core provided technical assistance for this work. VANTAGE was supported by Clinical and Translational Science Award (Grant 5UL1 RR024975-03), the Vanderbilt Ingram Cancer Center (Grant P30 CA068485), the Vanderbilt Vision Center (Grant P30 EY08126), and National Center for Research Resources, NIH (Grant G20 RR030956). Flow sorting experiments were performed in the Vanderbilt University Medical Center Flow Cytometry Shared Resource and were supported by the Vanderbilt Ingram Cancer Center (Grant P30 CA068485) and the Vanderbilt Digestive Disease Research Center (Grant P30 DK058404).
S.O.D. and J.E.B. designed and performed the experiments, analyzed the data, and wrote the manuscript. T.D.G. and J.C.R. designed experiments and wrote the manuscript. K.E.B. performed experiments and wrote the manuscript. N.J.M. designed experiments. K.L.Y., M.Z.M., J.E.B., B.I.R., X.Y., and R.H. performed experiments and performed data analysis. M.Z.M., J.E.B., and A.A. analyzed data and created figures.
The online version of this article contains supplemental material.
Abbreviations used in this article
- DIO
- diet-induced obesity
- ECM
- extracellular matrix
- HFD
- high-fat diet
- iNOS
- inducible NO synthase
- LFD
- low-fat diet
- MHC II
- MHC class II
- PD-1
- programmed cell death protein 1
- PD-L1
- programmed cell death protein ligand 1
- scRNAseq
- single-cell RNA sequencing
- TAM
- tumor-associated macrophage
- TIL
- tumor-infiltrating lymphocyte
- Received October 26, 2020.
- Accepted October 5, 2021.
- Copyright © 2021 by The American Association of Immunologists, Inc.
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