Endogenously High Omega-3 levels lead to a less exhausted T cell phenotype in tumor microenvironment

Authors

• Y Zhang
• B Moss

Abstract

Cancer causes multiple changes in the cellular pool of nutrients and macromolecules, including lipids. Tumors switch to the de novo lipid pathway and preferentially accumulate some lipids while excluding others, such as omega-3 (n-3) fatty acids and bioactive lipids derived from them, from the tumor microenvironment. These lipids, known as specialized pro-resolving lipids (SPM), may affect cancer development. Although their roles in decreased cancer risk and inflammation are well studied, their effects on anti-tumor immunity are still poorly understood. Here, we report the consequences of high n-3 levels on tumor growth and anti-tumor immunity. We have utilized a FAT-1 transgenic mouse model with an endogenously high n-3: n-6 ratio due to a transgenic enzyme making n-3 fatty acids and EO771 mammary tumor model. Our data show a decreased tumor growth rate in FAT-1 mice associated with increased tumor-infiltrating cells (TILs). In preliminary studies, we found that CD8 and CD4 T-cells in TILs isolated from tumors growing in FAT-1 mice display a more active and proliferative phenotype. Also, the T-cells had decreased exhaustion markers such as TIM-3, LAG-3, and TIGIT in the TILs isolated from tumors growing in FAT-1 animals, and there were fewer FOXP-3 positive T-cells. Together our data suggest a less suppressive anti-tumor immune environment in FAT-1 animals. Currently, we are performing mechanistic studies to understand the role of high omega-3 in the expression and function of these exhaustion markers. We are also exploring the therapeutic benefit of CPI and cancer vaccines in combination with high omega-3 fatty acids.

Scientific Focus Area: Immunology

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