Tumor Microenvironment: A Metabolic Player that Shapes the Immune Response

Abstract

Immune cells survey and patrol throughout the body and sometimes take residence in niche environments with distinct cellular subtypes and nutrients that may fluctuate from those in which they matured. Rooted in immune cell physiology are metabolic pathways and metabolites that not only deliver substrates and energy for growth and survival, but also instruct effector functions and cell differentiation. Unlike cancer cells, immune cells are not subject to a "Darwinian evolutionary pressure" that would allow them to adapt to developing tumors but are often irrevocably affected to local nutrient deprivation. Thus, immune cells must metabolically adapt to these changing conditions in order to perform their necessary functions. On the other hand, there is now a growing appreciation that metabolic changes occurring in cancer cells can impact on immune cell functionality and contribute to tumor immune evasion, and as such, there is a considerable and growing interest in developing techniques that target metabolism for immunotherapy. In this review, we discuss the metabolic plasticity displayed by innate and adaptive immune cells and highlight how tumor-derived lactate and tumor acidity restrict immunity. To our knowledge, this review outlines the most recent insights on how tumor microenvironment metabolically instructs immune responsiveness.

Keywords: cancer; immunity; lactate; metabolism; microenvironment; nutrients; tumor acidity.

Figure 1

Metabolic competition in the tumor microenvironment is a driver of T cell responsiveness. As mentioned in the review’s text, the increased metabolism displayed by tumor cells consumes most nutrients from the surrounding microenvironment, and as a consequence, impacts on the intrinsic metabolism of T cells, with a decreased ability to produce cytokines (especially IFN-γ) and to develop into tumor-specific T effector cells, leading to T cell hypo-responsiveness and increased tumor progression (nutrient-restricted T cells in red). Conversely, in a nutrient-enriched microenvironment, T cell metabolism increases (glycolysis) and leads to an improved IFN-γ production and immune response (T cells nutrient sufficient in green). IFN-γ: Interferon gamma.

Figure 2

Tumor acidity impacts on immune cell function. As illustrated in the review’s text, tumor acidity acts as an immune escape mechanism by which tumor cells (whose heterogeneity is depicted by tumor cells of different colors) repress the activity of anti-tumor immune effectors (including T cells, natural killer (NK) cells, and dendritic cells (DC)), and also favor the conversion of macrophages toward a non-inflammatory M2 phenotype, potentiated by hypoxia and altered metabolism, thereby creating an hostile milieu for T cells, NK cells, and DC. However, the possible effect of pH on antibody activity is still controversial and not fully elucidated. IL-2: Interleukine 2, TNF-α: Tumor necrosis factor-α, IFN-γ: Interferon gamma, TCR: T cell receptor, IL-12: Interleukine 12, IL-10: Interleukine 10, DC: Dendritic cell, NK: Natural killer, Fc: Fragment crystallizable.