Beyond the Lactate Paradox: How Lactate and Acidity Impact T Cell Therapies against Cancer

Abstract

T cell therapies, including CAR T cells, have proven more effective in hematologic malignancies than solid tumors, where the local metabolic environment is distinctly immunosuppressive. In particular, the acidic and hypoxic features of the tumor microenvironment (TME) present a unique challenge for T cells. Local metabolism is an important consideration for activated T cells as they undergo bursts of migration, proliferation and differentiation in hostile soil. Tumor cells and activated T cells both produce lactic acid at high rates. The role of lactic acid in T cell biology is complex, as lactate is an often-neglected carbon source that can fuel TCA anaplerosis. Circulating lactate is also an important means to regulate redox balance. In hypoxic tumors, lactate is immune-suppressive. Here, we discuss how intrinsic- (T cells) as well as extrinsic (tumor cells and micro-environmental)-derived metabolic factors, including lactate, suppress the ability of antigen-specific T cells to eradicate tumors. Finally, we introduce recent discoveries that target the TME in order to potentiate T cell-based therapies against cancer.

Dissecting Tumor Growth: The Role of Cancer Stem Cells in Drug Resistance and Recurrence

“…One of the many consequences of low oxygen in the tumor environment, and HIF stabilization therein, is the induction of glycolytic enzymes and a shift from oxidative phosphorylation to glycolysis for energy production. This results in the enhanced production of metabolic acids, such as lactic acid, and acidification of the microenvironment, promoting CSC-like phenotypes [ 90 , 91 ]. These changes lead to the microenvironment signals, i.e., HIFs result in EMT that forces the cells to achieve the stem cell state, thus promoting the CSC phenotype and even metastasis.…”

Immune Cell Metabolic Fitness for Life

“…The tumor microenvironment is unfavorable to the metabolic needs of invading immune cells. Low oxygen, high acidity, and limited resources blunt the potential for invading lymphocytes [ 36 , 37 , 38 ]. The pH of the environment is a critical factor, and when acidic, damages healthy tissue, dampens immune responses, and primes the area for metastasis and invasion [ 39 , 40 , 41 , 42 ].…”

“…This may be a key reason why CAR T cell strategies struggle with solid tumors. Tumors can produce acid from several sources, most notably the extrusion of lactate following glycolysis [ 39 ], and both acidity and lactate have been shown to reduce T cell activity [ 38 , 42 , 43 ]. Interestingly, as effector T cells are highly glycolytic, they may suppress themselves.…”

“…Work on lactate and pH in the tumor microenvironment is far from complete. While there are numerous approaches to managing lactate levels, such as inhibition of lactic acid dehydrogenase, inhibition of lactate transport, and neutralizing environmental pH, lactate is a critical metabolite whose role in immune cell and cancer cell bioenergetics is complex [ 38 ]. Recently, Ye et al have employed a gain of function screen in primary T cells using CRISPR to express proteins not normally present in primary T cells and then categorized the hits by effector function.…”

“…It is not fully clear how cytokine release syndrome is initiated, although there is evidence that engineered CAR T cells may stimulate neighboring cells to induce cytokine release and signaling [ 87 ]. Highly specific, targeted CAR T cell activation, such as with bi-specific antibodies, is one approach to minimize activation of other immune cells [ 38 , 64 , 65 , 88 ]. Ample research is dedicated to examining cytokine release syndrome because it is not only an issue with CAR T therapy, but with many infectious diseases.…”