Starved and Asphyxiated: How Can CD8+ T Cells within a Tumor Microenvironment Prevent Tumor Progression

Abstract

Although cancer immunotherapy has achieved significant breakthroughs in recent years, its overall efficacy remains limited in the majority of patients. One major barrier is exhaustion of tumor antigen-specific CD8+ tumor-infiltrating lymphocytes (TILs), which conventionally has been attributed to persistent stimulation with antigen within the tumor microenvironment (TME). A series of recent studies have highlighted that the TME poses significant metabolic challenges to TILs, which may contribute to their functional exhaustion. Hypoxia increases the expression of coinhibitors on activated CD8+ T cells, which in general reduces the T cells’ effector functions. It also impairs the cells’ ability to gain energy through oxidative phosphorylation. Glucose limitation increases the expression of programed cell death protein-1 and reduces functions of activated CD8+ T cells. A combination of hypoxia and hypoglycemia, as is common in solid tumors, places CD8+ TILs at dual metabolic jeopardy by affecting both major pathways of energy production. Recently, a number of studies addressed the effects of metabolic stress on modulating CD8+ T cell metabolism, differentiation, and functions. Here, we discuss recent findings on how different types of metabolic stress within the TME shape the tumor-killing capacity of CD8+ T cells. We propose that manipulating the metabolism of TILs to more efficiently utilize nutrients, especially during intermittent periods of hypoxia could maximize their performance, prolong their survival and improve the efficacy of active cancer immunotherapy.

Role of the immunosuppressive microenvironment in immunotherapy

“…Dysregulated cancer cell growth can lead to tumor intrinsic immunosuppressive features, such as regions of hypoxia and elevated levels of lactate that can inhibit effector T cell function 34 . However, the majority of immune suppression is due to the presence of normal immune regulatory cells and molecules within the tumor that inhibit T-cell priming or suppress cytotoxic T cell function 35, 36. Of these, immune checkpoint–related molecules have garnered the most attention, with proven clinical success of ICIs.…”

Efficacy of PD-1 Blockade Is Potentiated by Metformin-Induced Reduction of Tumor Hypoxia

“…Hypoxia is generally considered to be immunosuppressive, although previous studies employing HIF1α, VHL-, and PHD-deficient T cells have revealed that the role of these proteins in T-cell differentiation and function is likely complex (7,8). Studies with ‘true’ hypoxia remain unclear, as apparent roles for oxygen tension in differentiation versus effector function can be disparate (9).…”

Regulation of T cell immunity by cellular metabolism

“…CPT1, as the rate-limiting enzyme in FAO, is critical for the metabolism of FAO. The phosphorylation of ACC1/2 and SREBP-1c inhibits FAS but activates FAO [90].…”

“…A previous study reported that changes in T cell metabolic regulation inhibit the antitumor capability of T cells, leading to tumor escape [88]. In the tumor microenvironment, metabolic interference and nutrients competition exist between cancer and T cells, which are important to drive cancer development [89,90]. Tumor cells require a large amount of energy metabolism to proliferate by increasing glycolysis and glucose uptake from the surrounding environment [91].…”