Poorly perfused tumor regions harbor T cells with a glucose-dependent effector phenotype

Effector T lymphocytes are avid nutrient consumers, but can function in nutrient-poor tumor microenvironments. Availability of key nutrients such as glucose inside the tumor is not homogeneous, and how tumor-infiltrating T lymphocytes (TILs) differ between regions with better and poorer blood perfusion is not well known. Here we show that in vitro-stimulated TILs can induce substantial production of hallmark glucose-dependent cytokines under glucose concentrations 20 times lower than in blood. In vivo, effector TILs in tumor regions with poor access to blood show comparable capacity for inducing IFNγ and granzyme B to TILs with fuller accessibility; exhibit an enhanced type I IFN response supported by local myeloid cells; and unexpectedly, have reduced expression of immune checkpoint and Treg-associated markers. TILs with poor blood accessibility also have lower biosynthetic activity than highly blood-accessible TILs, yet both compartments depend fundamentally on glucose for ATP production. Thus, effector T lymphocytes in poorly perfused tumor regions can maintain specific glucose-dependent responses, and might be partially protected from inhibitory and exhausting pressure from the tumor microenvironment.