Metabolic Barriers to Tumor Immunity in Pancreatic Cancer

The microenvironment of many solid tumors impedes many immunotherapeutic treatments by inhibiting the effector functions of many classes of anti-tumor immune cells, including effector T cells. Many components are thought to contribute to the immunosuppressive nature of the tumor microenvironment, but recently abnormal availability of critical nutrients required for immune cell function has emerged as a key immunosuppressive factor. However, precisely which nutrient perturbations and how these tumor nutrient cues impact immune cell function has remained obscure. To identify the tumor nutrients regulating T cell function, we developed techniques to quantify nutrient levels in the microenvironment of solid tumors and cell culture model termed Tumor Interstitial Fluid Medium (TIFM) that enables us to grow and study T cell function under these nutritional constraints. Effector T cells cultured in TIFM exhibit profound dysfunction and we identified the components of TIFM that drive this dysfunction. In this talk, I will describe our work identifying nutrients that are deprived in the tumor microenvironment to impair anti-tumor immunity. I will also discuss our recent findings identifying immunosuppressive metabolites that accumulate in diverse tumors and the molecular mechanisms by which these metabolites impair T cell function.

Learning Objectives:

1. Review the experimental work that suggests the tumor microenvironment in pancreatic cancer limits anti-cancer immune cell effector functions.
2. Identify how nutrient levels in the tumor microenvironment are altered and limit anti-cancer immune cell function.
3. Classify how alterations in Kennedy pathway activity in T cells brought on by the tumor microenvironment impair T cell function.