Immune cell metabolism in the tumor microenvironment
During a productive immune response to cancer, naive tumor antigen-specific T cells become activated and produce a variety of effector molecules that mediate tumor clearance. However, T cells often experience a progressive decline in function and responsiveness during cancer, and without properly functioning T cells, tumors will continue to grow.
We have recently shown that this T cell dysfunction, or exhaustion, in cancer can result from a metabolic competition between tumors and T cells, which compete for the same nutrients in the tumor microenvironment. Competition for glucose alone can dampen the ability of tumor infiltrating T cells to engage aerobic glycolysis, which is required for their acquisition of full effector function and their ability to control tumor progression.
We also found that several checkpoint blockade antibodies, which are used clinically to treat cancer patients, can restore glucose in the tumor microenvironment, permitting T cell glycolysis and effector cytokine production. These findings suggest that new efforts to target cancer should incorporate the idea that metabolic competition occurs in tumors and greatly influences tumor progression.
Our new work focuses on understanding whether even transient nutrient restrictions can lead to permanent states of exhaustion in T cells.