Description

The good & the bad: Myeloid-derived suppressor cells (MDSC) are induced by high fat diet and leptin and protect against metabolic dysfunction, but promote tumor progression

S. Ostrand-Rosenberg, C. Figley, R. Long, T. Long & V. Clements

University of Maryland Baltimore County (UMBC), Baltimore, Maryland

Obesity is a risk factor for both cancer incidence and cancer mortality. The association of obesity and cancer is attributed to multiple factors, but the tightest linkage is the chronic, low grade inflammation that accompanies obesity, since chronic inflammation is an established cancer risk. MDSC are known facilitators of cancer progression. Because MDSC quantity and function are driven by chronic inflammation, we hypothesized that MDSC may accumulate in obese individuals and facilitate tumor growth by suppressing antitumor immunity. To test this hypothesis, tumor-bearing BALB/c and C57BL/6 mice on a high fat or low fat diet (HFD or LFD) were assessed for tumor progression and the metabolic dysfunction that is associated with obesity. HFD amplified the accumulation and immune suppressive potency of MDSC. Surprisingly, MDSC induced by HFD protected mice against diet-induced metabolic dysfunction and reduced HFD-associated inflammation, but increased the accumulation of fat. Although MDSC induced by HFD reduced metabolic dysfunction associated with HFD, they enhanced tumor progression and spontaneous metastasis, and reduced survival time. MDSC induced by HFD facilitated tumor growth by limiting the activation of tumor-reactive CD8⁺ T cells and by inhibiting T cell entry into solid tumors. Leptin, an adipokine that regulates appetite satiety and is over-expressed in obesity, drives MDSC accumulation and suppressive potency by enhancing T cell production of IFNγ, which in turn, supports MDSC differentiation and increases MDSC expression of the checkpoint inhibitor PDL1. Collectively, these studies reveal a new mechanism by which HFD and obesity contribute to cancer progression, and identify HFD-induced MDSC as major culprits for facilitating tumor growth while simultaneously protecting mice against diet-induced metabolic dysfunction.