Bader et al. showed that obesity-associated metabolic signaling and inflammatory cytokines induced PD-1 expression on tumor-associated macrophages (TAMs) in an mTORC1- and glycolysis-dependent manner. PD-1 in TAMs initiated a feedback mechanism that impaired glycolysis, phagocytosis, T cell stimulatory potential, and tumor immune surveillance. PD-1 blockade rescued macrophage metabolism and antitumor functions. Myeloid-specific PD-1 deficiency enhanced TAM glycolysis and antigen presentation capability, improved T cell-mediated anti-tumor immunity, and slowed tumor growth.
Contributed by Shishir Pant
ABSTRACT: Obesity is a leading risk factor for progression and metastasis of many cancers1,2, yet can in some cases enhance survival3-5 and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells6-8. Although obesity promotes chronic inflammation, the role of the immune system in the obesity-cancer connection and immunotherapy remains unclear. It has been shown that in addition to T cells, macrophages can express PD-19-12. Here we found that obesity selectively induced PD-1 expression on tumour-associated macrophages (TAMs). Type I inflammatory cytokines and molecules linked to obesity, including interferon-γ, tumour necrosis factor, leptin, insulin and palmitate, induced macrophage PD-1 expression in an mTORC1- and glycolysis-dependent manner. PD-1 then provided negative feedback to TAMs that suppressed glycolysis, phagocytosis and T cell stimulatory potential. Conversely, PD-1 blockade increased the level of macrophage glycolysis, which was essential for PD-1 inhibition to augment TAM expression of CD86 and major histocompatibility complex I and II molecules and ability to activate T cells. Myeloid-specific PD-1 deficiency slowed tumour growth, enhanced TAM glycolysis and antigen-presentation capability, and led to increased CD8+ T cell activity with a reduced level of markers of exhaustion. These findings show that obesity-associated metabolic signalling and inflammatory cues cause TAMs to induce PD-1 expression, which then drives a TAM-specific feedback mechanism that impairs tumour immune surveillance. This may contribute to increased cancer risk yet improved response to PD-1 immunotherapy in obesity.
Author Info: (1) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. (2) Department of Pathology, Microbiology, and Immunology, Vand
Author Info: (1) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. (2) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. (3) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. (4) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. (5) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (6) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (7) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. (8) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. (9) Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA. (10) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (11) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (12) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. (13) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. (14) Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. (15) Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, TN, USA. (16) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. (17) Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. (18) Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. (19) Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. (20) Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (21) Department of Medicine, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA. (22) Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada. (23) Department of Medicine, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA. (24) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. (25) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. (26) Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA. (27) Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA. (28) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA. (29) Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada. (30) Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada. (31) Department of Biostatistics, Vanderbilt University, Nashville, TN, USA. (32) Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. (33) Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. US Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA. (34) Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. jeff.rathmell@vumc.org. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA. jeff.rathmell@vumc.org. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. jeff.rathmell@vumc.org. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. jeff.rathmell@vumc.org.
