The Complex Integration of T-cell Metabolism and Immunotherapy

Abstract

Immune oncology approaches of adoptive cell therapy and immune checkpoint blockade aim to activate T cells to eliminate tumors. Normal stimulation of resting T cells induces metabolic reprogramming from catabolic and oxidative metabolism to aerobic glycolysis in effector T cells, and back to oxidative metabolism in long-lived memory cells. These metabolic reprogramming events are now appreciated to be essential aspects of T-cell function and fate. Here, we review these transitions, how they are disrupted by T-cell interactions with tumors and the tumor microenvironment, and how they can inform immune oncology to enhance T-cell function against tumors. SIGNIFICANCE: T-cell metabolism plays a central role in T-cell fate yet is altered in cancer in ways that can suppress antitumor immunity. Here, we discuss challenges and opportunities to stimulate effector T-cell metabolism and improve cancer immunotherapy.

Figure 1.. T cell metabolism drives T cell fate and function in to eliminate tumors.

Naïve T cells rely on oxidative metabolism (OXPHOS) and maintain robust mitochondrial quality control. After activation with co-stimulation through receptors including CD28 that activate the mTORC1 pathway, effector T cells increase glucose and glutamine (Gln) metabolism to support effector function. If antigen is cleared, effector cells can enter a long-lived memory state with stem cell-like properties. If antigen remains, as often occurs in long-term tumor elimination processes, inhibitory receptors such as PD-1 and CTLA4 can reshape T cell metabolism to reduce pathways that characterize effector T cells and lead to multiple metabolic impairments. Exhausted T cells demonstrate reduced glucose and glutamine metabolism, low quality dysfunctional mitochondrial, and a dependance on fatty acid oxidation (FAO). Potentially contributing to T cell disfunction in the tumor microenvironment are low levels of oxygen (pO2), low levels of tryptophan (Trp) metabolized by the kynurenine pathway including indoleamine 2,3-dioxygenase (IDO), low levels of arginine (Arg) metabolized by arginase (ARG1), high levels of lactate, and potentially competition for glucose with cancer cells. Figure created with Biorender.com.