Investigation of Divergent Metabolic Programs in the Tumor-Immune Microenvironment

Abstract

The current immune metabolism field has been using the term lactate and lactic acid interchangeably, with the notion that lactate and lactic acid are waste products of highly glycolytic cancer cells that negatively affects TIL function and viability to promote tumorigenesis. However, it is yet unclear whether lactate or its protonated counterpart lactic acid is responsible for the dampening of immune cell functions within the TIME. The in vitro cell culture studies aimed to delineate the impact of lactate and lactic acid in the context of cancer growth. Data showed that lactate alone significantly impairs cancer cell metabolism independent of the acidic pH environment. Additionally, therapeutic lactate treatment significantly increased the glycolytic activity and effector functions of CD8+ T-cells, contrary to the current understanding that lactate dampens immune cell functions. The comparison study between lactate and lactic acid further demonstrated that CD8+ T-cells undergo cell death that is dependent on pH levels, with approximately 50% of T-cell death occurring at pH level below 6.0, whereas cancer cells were able to metabolically adapt to the acidic environment and sustain growth. These findings provide a new perspective that challenges the current notion that lactate is considered a "pro-tumor" metabolite. In vivo metabolomics study of tumor cells and tumor-infiltrating CD8+ T-cells revealed that lactate initiates a divergent metabolic reprogramming in the two cell types. Systemic lactate treatment suppressed tumor glycolytic activities while boosting CD8+ T-cell glycolytic rate and effector function. Such divergent changes in two cell types provide a basis for developing potent antitumor responses in the complex heterogeneous tumor microenvironment. The impact of lactate on glycolytic flux modulation on both tumor cells and CD8+ T-cells, therefore, exposes a previously undefined difference in metabolic programs between the two cell types that can be exploited in the immune-suppressive tumor microenvironment