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. 2024 Jun;630(8018):968-975.
doi: 10.1038/s41586-024-07529-3. Epub 2024 Jun 12.

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

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

Jackie E Bader et al. Nature. 2024 Jun.

Erratum in

  • Author Correction: Obesity induces PD-1 on macrophages to suppress anti-tumour immunity.
    Bader JE, Wolf MM, Lupica-Tondo GL, Madden MZ, Reinfeld BI, Arner EN, Hathaway ES, Steiner KK, Needle GA, Hatem Z, Landis MD, Faneuff EE, Blackman A, Wolf EM, Cottam MA, Ye X, Bates ME, Smart K, Wang W, Pinheiro LV, Christofides A, Smith D, Boussiotis VA, Haake SM, Beckermann KE, Wellen KE, Reinhart-King CA, Serezani CH, Lee CH, Aubrey C, Chen H, Rathmell WK, Hasty AH, Rathmell JC. Bader JE, et al. Nature. 2024 Jul 9. doi: 10.1038/s41586-024-07794-2. Online ahead of print. Nature. 2024. PMID: 38982216 No abstract available.

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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