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

AI Article Synopsis

  • Obesity is linked to both increased cancer risk and potentially better responses to immunotherapy, particularly through the PD-1 pathway that affects immune cell function.
  • Tumour-associated macrophages (TAMs) show enhanced PD-1 expression in obese conditions, influenced by obesity-related cytokines and metabolic signals.
  • Blocking PD-1 improves macrophage activity and T cell activation, suggesting that obesity may create an environment that hampers immune response to tumors while still allowing for enhanced efficacy of PD-1-targeted therapies.

Article Abstract

Obesity is a leading risk factor for progression and metastasis of many cancers, yet can in some cases enhance survival and responses to immune checkpoint blockade therapies, including anti-PD-1, which targets PD-1 (encoded by PDCD1), an inhibitory receptor expressed on immune cells. 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. 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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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC11456854PMC
http://dx.doi.org/10.1038/s41586-024-07529-3DOI Listing

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