Obesity induces PD-1 on macrophages to suppress anti-tumour immunity

  • Nature. 2024 Jun;630(8018):968-975. doi: 10.1038/s41586-024-07529-3.
Jackie E Bader  1 ,  Melissa M Wolf  1 ,  Gian Luca Lupica-Tondo  1 ,  Matthew Z Madden  1 ,  Bradley I Reinfeld  2 ,  Emily N Arner  2 ,  Emma S Hathaway  1 ,  KayLee K Steiner  1 ,  Gabriel A Needle  3 ,  Zaid Hatem  2 ,  Madelyn D Landis  2 ,  Eden E Faneuff  1 ,  Amondrea Blackman  2 ,  Elysa M Wolf  4 ,  Matthew A Cottam  5 ,  Xiang Ye  1 ,  Madison E Bates  6 ,  Kyra Smart  6 ,  Wenjun Wang  6 ,  Laura V Pinheiro  7 ,  Anthos Christofides  8 ,  DuPreez Smith  9 ,  Vassiliki A Boussiotis  8 ,  Scott M Haake  2  10 ,  Kathryn E Beckermann  2  10 ,  Kathryn E Wellen  11 ,  Cynthia A Reinhart-King  6 ,  C Henrique Serezani  2  3 ,  Cheng-Han Lee  12 ,  Christa Aubrey  9 ,  Heidi Chen  13 ,  W Kimryn Rathmell  2  3  10 ,  Alyssa H Hasty  3  4  10  14 ,  Jeffrey C Rathmell  15  16  17  18
Affiliations
  • 1. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 2. Department of Medicine, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 3. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 4. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA.
  • 5. Department of Surgery, Division of Surgical Oncology and Endocrine Surgery, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 6. Department of Biomedical Engineering, Vanderbilt University, Nashville, TN, USA.
  • 7. Department of Biochemistry and Molecular Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 8. Department of Medicine, Division of Hematology-Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Harvard University, Boston, MA, USA.
  • 9. Department of Obstetrics and Gynecology, University of Alberta, Edmonton, Alberta, Canada.
  • 10. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA.
  • 11. Department of Cancer Biology, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
  • 12. Department of Laboratory Medicine and Pathology, University of Alberta, Edmonton, Alberta, Canada.
  • 13. Department of Biostatistics, Vanderbilt University, Nashville, TN, USA.
  • 14. US Department of Veterans Affairs, Tennessee Valley Healthcare System, Nashville, TN, USA.
  • 15. Department of Pathology, Microbiology, and Immunology, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
  • 16. Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
  • 17. Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. [email protected].
  • 18. Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. [email protected].
PMID: 38867043 DOI: 10.1038/s41586-024-07529-3
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.

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