Metabolic Regulation of T Cell Longevity and Function in Tumor Immunotherapy

Abstract

Summary Cancer immunotherapy is an increasingly successful strategy for the treatment of patients who have advanced or conventional therapy-resistant cancers. T cells are key mediators of tumor destruction and their specificity for tumor-expressed antigens is of paramount importance, but other T cell-intrinsic qualities such as durability, longevity and functionality also play important roles in determining the efficacy of immunotherapy. The cellular energetic pathways that are utilized by T cells play a key role in regulating each of these qualities. Metabolic activity, which both regulates and is regulated by cellular signaling pathways and epigenetics, also profoundly influences the trajectories of T cell differentiation and fate. In this review, we discuss how cell metabolism influences T cell anti-tumor activity, the metabolic qualities of highly-functional T cells and strategies to modulate metabolism for improving the immune response to tumors.

Alteration of Tumor Metabolism by CD4+ T Cells Leads to TNF-α-Dependent Intensification of Oxidative Stress and Tumor Cell Death

“…Adoptive immunotherapy has manifested significant, sometimes curative, therapeutic effects in treating certain types of cancer. Recent studies have shown that T cell metabolic attributes largely shape donor T cell persistence and memory development, which are key determinants of therapy efficacy (Kawalekar et al, 2016; Kishton et al, 2017; Sukumar et al, 2013). …”

Identification of a new pyruvate kinase M2 isoform (PKM2) activator for the treatment of non‐small‐cell lung cancer (NSCLC)

“…During T‐cell differentiation from naïve to terminally differentiated T cells, anabolic metabolism increases and generates biosynthetic intermediates, such as nucleotides, in a process similar to the Warburg effect. It has also been reported that reducing T‐cell glycolysis during T‐cell expansion for immunotherapy can maintain the T‐cell replicative capacity and longevity to mediate a successful immune anti‐cancer effect in vivo; this can be achieved using pharmacological interventions to modulate T‐cell metabolism . To date, there are few studies investigating PKM2 in relation to immune function.…”

The clock is ticking: the impact of ageing on T cell metabolism

“…Blocking glycolytic metabolism in young CD8 T cells has been shown to promote generation of long‐lived, functional memory populations, while enforcing glycolysis drives CD8 T cells towards a terminally differentiated state . One way to prevent accumulation of terminally differentiated senescent T cells and promote survival of functional memory T cells in advanced age could include inhibitors or regulators of glycolysis, such as 2‐deoxyglucose, which directly inhibits glycolysis or metformin, which indirectly decreases glycolysis via activation of AMPK …”