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

• 成果类型: Article
• 署名作者: Bader, Jackie E.; Wolf, Melissa M.; Lupica-Tondo, Gian Luca; Madden, Matthew Z.; Reinfeld, Bradley I.; Arner, Emily N.; Hathaway, Emma S.; Steiner, KayLee K.; Needle, Gabriel A.; Hatem, Zaid; Landis, Madelyn D.; Faneuff, Eden E.; Blackman, Amondrea; Wolf, Elysa M.; Cottam, Matthew A.; Ye, Xiang; Bates, Madison E.; Smart, Kyra; Wang, Wenjun; Pinheiro, Laura V.; Christofides, Anthos; Smith, DuPreez; Boussiotis, Vassiliki A.; Haake, Scott M.; Beckermann, Kathryn E.; Wellen, Kathryn E.; Reinhart-King, Cynthia A.; Serezani, C. Henrique; Lee, Cheng-Han; Aubrey, Christa; Chen, Heidi; Rathmell, W. Kimryn; Hasty, Alyssa H.; Rathmell, Jeffrey C.
• 署名单位: Vanderbilt University; Vanderbilt University; Vanderbilt University; Vanderbilt University; Vanderbilt University; Vanderbilt University; University of Pennsylvania; Harvard University; Harvard Medical School; Harvard University Medical Affiliates; Beth Israel Deaconess Medical Center; University of Alberta; Vanderbilt University; University of Pennsylvania; University of Alberta; Vanderbilt University; US Department of Veterans Affairs; Veterans Health Administration (VHA); VA Tennessee Valley Healthcare System
• 刊物名称: Nature
• ISSN/ISSBN: 0028-4392
• DOI: 10.1038/s41586-024-07529-3
• 发表日期: 2024-06-27
• 页码: 968-+
• 关键词: body-mass index; cancer; expression; mortality; cohort; RISK

摘要

Obesity is a leading risk factor for progression and metastasis of many cancers(1,2), yet can in some cases enhance survival(3-5) 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-1(9-12). 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-., 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.