2. Academic Validation
  3. Obesity induces PD-1 on macrophages to suppress anti-tumour immunity

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

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. jeff.rathmell@vumc.org.
  • 16 Vanderbilt Center for Immunobiology, Vanderbilt University Medical Center, Nashville, TN, USA. jeff.rathmell@vumc.org.
  • 17 Department of Molecular Physiology and Biophysics, Vanderbilt University, Nashville, TN, USA. jeff.rathmell@vumc.org.
  • 18 Vanderbilt-Ingram Cancer Center, Vanderbilt University Medical Center, Nashville, TN, USA. jeff.rathmell@vumc.org.
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.

Figures
Products
嗨！很高兴为您提供帮助！

尊敬的 MCE 客户您好，
请您选择所在区域，我们将转接对应客服为您服务！

热门区域

A

B

C

F

G

H

J

L

N

Q

S

T

X

Y

Z

热 A B C F G H J L N Q S T X Y Z