Cancer acidity: An ultimate frontier of tumor immune escape and a novel target of immunomodulation

Abstract

The link between cancer metabolism and immunosuppression, inflammation and immune escape has generated major interest in investigating the effects of low pH on tumor immunity. Indeed, microenvironmental acidity may differentially impact on diverse components of tumor immune surveillance, eventually contributing to immune escape and cancer progression. Although the molecular pathways underlying acidity-related immune dysfunctions are just emerging, initial evidence indicates that antitumor effectors such as T and NK cells tend to lose their function and undergo a state of mostly reversible anergy followed by apoptosis, when exposed to low pH environment. At opposite, immunosuppressive components such as myeloid cells and regulatory T cells are engaged by tumor acidity to sustain tumor growth while blocking antitumor immune responses. Local acidity could also profoundly influence bioactivity and distribution of antibodies, thus potentially interfering with the clinical efficacy of therapeutic antibodies including immune checkpoint inhibitors. Hence tumor acidity is a central regulator of cancer immunity that orchestrates both local and systemic immunosuppression and that may offer a broad panel of therapeutic targets. This review outlines the fundamental pathways of acidity-driven immune dysfunctions and sheds light on the potential strategies that could be envisaged to potentiate immune-mediated tumor control in cancer patients.

Improving immune–vascular crosstalk for cancer immunotherapy

“…Last, hypoxia along with tumour cell necrosis, increase the extracellular concentrations of the immune-inhibitory metabolites adenosine and lactate. 52–55 The accumulation of lactate further leads to metabolic lactic acidosis (a low pH in the blood due to build up of lactic acid) and results in impaired cytotoxic T cell functions by interfering with T cell receptor (TCR)–triggered production of interferon-γ (IFNγ) 56 . These processes act together to inhibit effector immune cell maturation and promote T cell anergy and exhaustion (Fig 1).…”

Sculpting tumor microenvironment with immune system: from immunometabolism to immunoediting

“…The high abundance of lactate results in plastic remodeling of cytokinome and suppresses proliferation and mobility of cytotoxic T lymphocytes and NK cells, but supports formation of pro-tumorigenic TAMs and T regs [49,50]. Moreover, lactate may support T reg differentiation and survival in a MCT4-dependent manner [52,53]. Moreover, lactate may support T reg differentiation and survival in a MCT4-dependent manner [52,53].…”

Immunometabolism in cancer at a glance

“…In line with this, increased CO 2 production through the pentose phosphate pathway in cancer cells has been linked to an acidification of the tumor microenvironment (Kato et al, 2013). As broadly reviewed by Huber et al (2017), low pH negatively impacts the effector functions of both innate and adaptive immune cells. This was first described by Fischer et al, who demonstrated that low extracellular pH (pHe: 5.8) leads to decreased cytokine production and to a loss of cytotoxic effector functions without affecting cell viability (Fischer et al, 2000a,b; Muller et al, 2000).…”

“…This was first described by Fischer et al, who demonstrated that low extracellular pH (pHe: 5.8) leads to decreased cytokine production and to a loss of cytotoxic effector functions without affecting cell viability (Fischer et al, 2000a,b; Muller et al, 2000). The effect of low pH on cytokine production by T cells correlated with impaired signaling pathways involving STAT5, ERK, AKT, p38 and NFAT (Huber et al, 2017). Importantly, buffering of low pH with bicarbonate therapy increased T-cell infiltration and impaired tumor growth.…”