Suppressive effects of the obese tumor microenvironment on CD8 T cell infiltration and effector function
Lydia Dyck, Hannah Prendeville, Mathilde Raverdeau, Mieszko M. Wilk, Róisín M. Loftus, Aaron Douglas, Janet McCormack, Bruce Moran, Michael Wilkinson, Evanna L. Mills, Michael Doughty, Aurélie Fabre, Helen Heneghan, Carel LeRoux, Andrew E. Hogan, Edward T. Chouchani, Donal O’Shea, Donal J. Brennan, Lydia Lynch
Abstract
Obesity is one of the leading preventable causes of cancer; however, little is known about the effects of obesity on anti-tumor immunity. Here, we investigated the effects of obesity on CD8 T cells in mouse models and patients with endometrial cancer. Our findings revealed that CD8 T cell infiltration is suppressed in obesity, which was associated with a decrease in chemokine production. Tumor-resident CD8 T cells were also functionally suppressed in obese mice, which was associated with a suppression of amino acid metabolism. Similarly, we found that a high BMI negatively correlated with CD8 infiltration in human endometrial cancer and that weight loss was associated with a complete pathological response in six of nine patients. Moreover, immunotherapy using anti-PD-1 led to tumor rejection in lean and obese mice and partially restored CD8 metabolism and anti-tumor immunity. These findings highlight the suppressive effects of obesity on CD8 T cell anti-tumor immunity, which can partially be reversed by weight loss and/or immunotherapy.