Nature. 2024 Jun 12.
Jackie E Bader,
Melissa M Wolf,
Gian Luca Lupica-Tondo,
Matthew Z Madden,
Bradley I Reinfeld,
Emily N Arner,
Emma S Hathaway,
KayLee K Steiner,
Gabriel A Needle,
Zaid Hatem,
Madelyn D Landis,
Eden E Faneuff,
Amondrea Blackman,
Elysa M Wolf,
Matthew A Cottam,
Xiang Ye,
Madison E Bates,
Kyra Smart,
Wenjun Wang,
Laura V Pinheiro,
Anthos Christofides,
DuPreez Smith,
Vassiliki A Boussiotis,
Scott M Haake,
Kathryn E Beckermann,
Kathryn E Wellen,
Cynthia A Reinhart-King,
C Henrique Serezani,
Cheng-Han Lee,
Christa Aubrey,
Heidi Chen,
W Kimryn Rathmell,
Alyssa H Hasty,
Jeffrey C Rathmell.
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.