Microenvironmental influences on T cell immunity in cancer and inflammation

Abstract

T cell metabolism is dynamic and highly regulated. While the intrinsic metabolic programs of T cell subsets are integral to their distinct differentiation and functional patterns, the ability of cells to acquire nutrients and cope with hostile microenvironments can limit these pathways. T cells must function in a wide variety of tissue settings, and how T cells interpret these signals to maintain an appropriate metabolic program for their demands or if metabolic mechanisms of immune suppression restrain immunity is an area of growing importance. Both in inflamed and cancer tissues, a wide range of changes in physical conditions and nutrient availability are now acknowledged to shape immunity. These include fever and increased temperatures, depletion of critical micro and macro-nutrients, and accumulation of inhibitory waste products. Here we review several of these factors and how the tissue microenvironment both shapes and constrains immunity.

Keywords: T cell; cancer; immunometabolism; inflammation; microenvironment.

Fig. 1

Chemical and physical components of the tissue microenvironment that can modulate immunity. A Changes to micronutrients, including iron and potassium, regulate T cell function and survival from ferroptosis. B Increased H + and decreased pH also play important roles in T cell metabolism and fate. C Fever and high temperatures directly impact T cells to promote inflammatory states

Fig. 2

Obesity leads to both systemic and local changes to T cell microenvironments. Obesity or weight loss can have striking effects on T cell metabolism in the obesity paradox in which tumors are promoted yet sensitized to anti-PD1

Fig. 3

The tumor microenvironment and metabolic immune suppression. Obesity leads to chronic systemic and local inflammation. Adipose-resident CD8 T cells can be more naïve but are also sensitized to reactivate with PD-1 blockade. Many factors contribute to this obesity paradox, including elevated lactate, decreased glucose, and altered amino acids