Abstract

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.

Highlights

  • The obesity epidemic is a worldwide problem

  • PyMT mice were fed either a normal diet (ND) or high-fat diet (HFD), and the results showed that the HFD accelerated tumour initiation and was associated with increased tumour weights, tumour volumes, and tumour counts as well as elevated body weights (Fig. 1a,b)

  • We compared the gene expression profiles of the tumours of the ND-fed PyMT mice and those of the HFD-fed PyMT mice by performing quantitative RT-PCR, but the results showed no significant differences in the expression of macrophage markers (F4/80, CD11b, CD11c, CD206, and CD163), proinflammatory cytokines (Il1b, Il6, Il10, and Ifng), angiogenic markers (Igf[1], Hgf, Angpt[1], Angpt[2], Tie[2], and Vegfa), myeloid chemoattractants (Ccl[2] and Ccl7), Leptin, or Lepr between the two groups (Fig. 1c)

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Summary

Introduction

The obesity epidemic is a worldwide problem. Obesity is linked to a number of complications, such as diabetes, dyslipidaemia, cardiovascular disease, kidney disease, nonalcoholic steatohepatitis, obstructive sleep apnoea and cancer[1]. The M1/M2 polarization model seems to be oversimplified, M1-like macrophages are considered to be anti-tumourigenic, while M2-like macrophages are considered to be pro-tumourigenic[10] Immunomodulatory cells such as M2-like macrophages modify the tumour microenvironment by secreting immunosuppressive factors, angiogenic factors, and proinflammatory cytokines[11,12,13]. In chronic infectious diseases and cancers, CD8+ effector T cells gradually lose their ability to secrete IFNγ, IL-2, and TNFα due to continuous T-cell antigen receptor (TCR) stimulation by viral and tumour antigens[14,15] These T cells are referred to as exhausted T cells, and they lack proliferative activity and cytotoxic functions[16,17]. We hypothesized that T cell exhaustion is involved in the mechanism underlying high-fat diet (HFD)-induced tumourigenesis, and we conducted this study to test our hypothesis

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