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.
肥胖是导致多种癌症进展和转移的主要风险因素，但在某些情况下，肥胖会提高患者的存活率，并增强患者对免疫检查点阻断疗法的反应，包括针对免疫细胞上表达的抑制受体PD-1（由PDCD1编码）的抗PD-1疗法。虽然肥胖会促进慢性炎症，但免疫系统在肥胖与癌症的关系和免疫疗法中的作用仍不清楚。研究表明，除T细胞外，巨噬细胞也能表达PD-1。在这项研究中，我们发现肥胖会选择性地诱导肿瘤相关巨噬细胞（TAMs）表达PD-1。Ⅰ型炎症细胞因子和与肥胖有关的分子，包括干扰素-γ、肿瘤坏死因子、瘦素、胰岛素和棕榈酸酯，以依赖于mTORC1和糖酵解的方式诱导巨噬细胞PD-1的表达。然后，PD-1向TAMs 提供负反馈，抑制糖酵解、吞噬和T细胞刺激潜能。相反，PD-1阻断会增加巨噬细胞的糖酵解水平，这对PD-1抑制增强TAM表达CD86、主要组织相容性复合体I和II分子以及激活T细胞的能力至关重要。髓系特异性PD-1的缺乏减缓了肿瘤的生长，增强了TAM的糖酵解和抗原递呈能力，并导致CD8+T细胞活性增加，衰竭标志物水平降低。这些研究结果表明，与肥胖相关的代谢信号和炎症线索会导致TAM诱导PD-1表达，进而驱动TAM特异性反馈机制，损害肿瘤免疫监视。这可能会导致肥胖症患者患癌风险增加，但对PD-1免疫疗法的反应却有所改善。
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. 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. Epub 2024 Jun 12. PMID: 38867043.
