Linkage of CD8⁺ T cell exhaustion with high-fat diet-induced tumourigenesis

Obesity increases the risk of cancer. Increased levels of hormones (such as oestrogen, insulin, insulin-like growth factor, and leptin), free fatty acid-induced production of reactive oxygen species, an altered intestinal microbiome and chronic inflammation are known to be associated with an increased cancer risk in obese subjects. However, the mechanism underlying the connection between obesity and cancer development remains elusive. Here, we show that a high-fat diet (HFD) promotes tumour initiation/progression and induces a phenotypic switch from PD-1^- CD8⁺ non-exhausted T cells to PD-1⁺ CD8⁺ exhausted T cells in a murine breast cancer model. While PD-1^- CD8⁺ non-exhausted T cells predominated in the mammary glands of normal diet (ND)-fed mice, PD-1⁺ CD8⁺ exhausted T cells accumulated in the developing tumours of HFD-fed mice. Gene expression profiles indicated that PD-1⁺ CD8⁺ T cells expressed higher levels of the tumour-trophic gene Opn and lower levels of the cytotoxic genes Ifng and Gzmb than did PD-1^- CD8⁺ T cells. Our study provides a possible mechanistic linkage between obesity and cancer.