Manipulation of metabolic pathways to promote stem-like and memory T cell phenotypes for immunotherapy

Abstract

Utilizing the immune system’s capacity to recognize and kill tumor cells has revolutionized cancer therapy in recent decades. Phenotypic study of antitumor T cells supports the principle that superior tumor control is achieved by cells with more long-lived memory or stem-like properties as compared to terminally differentiated effector cells. In this Mini-Review, we explore recent advances in profiling the different metabolic programs that both generate and define subsets of memory T cells. We additionally discuss new experimental approaches that aim to maximize the durability and sustained antitumor response associated with memory T cells within the unique immunosuppressive conditions of the tumor microenvironment, such as engineered attempts to overcome hypoxia-induced changes in mitochondrial function, the inhibitory effects of tumor metabolites, and exploitation of more recently-defined metabolic pathways controlling T cell memory fate such as glycogen metabolism.

Metabolic priming of GD2TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence

“…A stem cell memory state is often defined by the expression of surface markers such as CD45RA, CD62L, and CCR7 13, 46 an oxidative versus a glycolytic metabolism, commonly seen in activated effector T-cells, 22, 47 and lower glucose consumption. 28, 48, 49 ( Fig. 2B ).…”

“…Compared to Control cells, MP TRAC -CAR T cells had higher populations of CD62L + /CCR7 + cells, lower lactate production, glucose consumption, and ECAR post-manufacturing, making them distinctly more T SCM- like 13,16,44 ( Fig. 2C, 2F, 3A ).…”

“…These characteristics have been observed in less differentiated cells, notably T SCM cells. 13,49 To assess the impact of these critical quality attributes on potency in vivo, TRAC-CAR T cells of both groups were infused into a xenograft NSG mouse model of neuroblastoma. There was similar tumor regression across the two groups (Fig.…”

Metabolic priming of GD2 TRAC-CAR T cells during manufacturing promotes memory phenotypes while enhancing persistence

“…We classified T cell phenotypes by classic definitions: T SCM (stem cell memory), T CM (central memory), T EM (effector memory), and T EFF (effector). A stem cell memory state is often defined by the expression of surface markers such as CD45RA, CD62L, and CCR7 13 , 46 an oxidative versus a glycolytic metabolism, commonly seen in activated effector T cells, 18 , 47 and lower glucose consumption 29 , 48 , 49 ( Figure 2 B). We defined T SCM TRAC- CAR T cells as CCR7 + /CD62L + , which indicates increased capacity for lymphoid homing.…”

The role of tumor metabolism in modulating T-Cell activity and in optimizing immunotherapy

“…However, this response rate is still far from optimal, underscoring the need to either develop other treatment options or modify current approaches. As discussed throughout this review, cancer cells can suppress an antitumor response by depleting essential nutrients or reducing the metabolic fitness of tumor-infiltrating cells ( 230 , 231 ). Therefore, tailoring immune responses by manipulating cellular metabolic pathways may improve clinical outcomes.…”