Mechanisms by which obesity regulates inflammation and anti-tumor immunity in cancer

Abstract

Obesity is associated with an increased risk for 13 different cancers. The increased risk for cancer in obesity is mediated by obesity-associated changes in the immune system. Obesity has distinct effects on different types of inflammation that are tied to tumorigenesis. For example, obesity promotes chronic inflammation in adipose tissue that is tumor-promoting in peripheral tissues. Conversely, obesity inhibits acute inflammation that rejects tumors. Obesity therefore promotes cancer by differentially regulating chronic versus acute inflammation. Given that obesity is chronic, the initial inflammation in adipose tissue will lead to systemic inflammation that could induce compensatory anti-inflammatory reactions in peripheral tissues to suppress chronic inflammation. The overall effect of obesity in peripheral tissues is therefore dependent on the duration and severity of obesity. Adipose tissue is a complex tissue that is composed of many cell types in addition to adipocytes. Further, adipose tissue cellularity is different at different anatomical sites throughout the body. Consequently, the sensitivity of adipose tissue to obesity is dependent on the anatomical location of the adipose depot. For example, obesity induces more inflammation in visceral than subcutaneous adipose tissue. Based on these studies, the mechanisms by which obesity promotes tumorigenesis are multifactorial and immune cell type-specific. The objective of our paper is to discuss the cellular mechanisms by which obesity promotes tumorigenesis by regulating distinct types of inflammation in adipose tissue and the tumor microenvironment.

Keywords: And myeloid-derived suppressor cells; Anti-Tumor immunity; CD8+T cells; Inflammation; Natural killer cells; Obesity.

Fig.1.. Adipose tissue inflammation in obesity.

Adipose tissue is highly responsive to obesity-induced inflammation. The increase in MCP-1, leptin, cytotoxic CD8 T cells, and activated neutrophils recruit and polarize proinflammatory M1-macrophages in adipose tissue in obesity. There is increased development of proinflammatory TH1 and TH17 cells, which by releasing INF_γ and IL-17 inhibit Tregs and stimulate neutrophils, respectively. Obesity-associated adipose tissue inflammation increases circulating TNF-α, IL-6, and leptin. MCP-1 = Monocyte Chemoattractant Protein 1, TNFα = Tumor necrosis factor-alpha, IL-6 = Interleukin-6, M1 = M1-stage Macrophage, IL-7 = Interleukin-17, TH17 = T helper 17, TH1 = T helper 1, Treg = Regulatory T cells, INF_γ = Interferon-gamma, IL-10, Interleukin-10.

Fig. 2.. T-cell exhaustion in obesity.

Increased leptin in obesity acts on cytotoxic CD8 T cells to induce signaling that promotes the phosphorylation of STAT3 (Tyr705) which in turn activates the STAT3 response element within the enhancer of the PD-1 gene which leads to increased PD-1 expression by T cells. The binding of T cell-expressed PD-1 to cancer cell-expressed PD-L1 induces signaling in CD8 T cells that inactivates the effector function of T cells, leading to an exhausted T cell state. P-STAT3 = Phosphorylated-Signal Transducer And Activator Of Transcription 3 (Tyr705), PD-1 = Programmed cell death protein 1, PD-L1 = Programmed Death-1 (PD-1) Ligand 1.

Fig. 3.. T cell inactivation in obesity.

There is a competition between T cells and cancer cells for limiting amounts of FFAs in the tumor interstitium. In lean mice, reduced utilization of FFAs by cancer cells due to upregulation of PHD3 promotes the flow of FFAs into T cells. In obese mice, reduced PHD3 promotes FFA utilization by cancer cells, which diverts the flow of FFAs away from T cells. PHD3 = Prolyl hydroxylase 3, FFA = Free Fatty Acids, FAO = Fatty Acid Oxidation.

Fig. 4.. Inhibition of NK cells in obesity.

In lean mice, mTOR signaling, P300, and MYC transcriptional proteins mediate the increase in cellular metabolism that is needed for NK polarization and the release of cytotoxic enzymes onto cancer cells. In obese mice, the uptake of lipids by NK cells leads to the formation of cytoplasmic lipid droplets (LDs) that inhibit mTOR signaling and destabilize P300 and MYC. This compromises cellular metabolism that is needed for the polarization and release of cytolytic enzymes by NK cells onto cancer cells. NK = Natural Killer, mTOR = mechanistic target of rapamycin, P300 = E1A Binding Protein P300, MYC = MYC Proto-Oncogene, BHLH Transcription Factor, GzmB = Granzyme B, PFN = Profilin 1, LD = lipid droplet.

Fig. 5.. Cancer-associated adipocytes

Cancer-associated adipocytes are in direct contact with cancer cells. Cancer cell-secreted factors act on adipocytes to induce lipolysis and the liberated FFAs are transferred to cancer cells for metabolism. Delipidation of adipocytes triggers de-differentiation into multiple cell types, including myofibroblasts, immune-like cells, and adipocyte progenitor cells that collectively increase cellular heterogeneity within the tumor microenvironment (TME), which promotes tumorigenesis. FFAs = Free fatty acids, TME = tumor microenvironment.