Neutralization of Tumor Acidity Improves Antitumor Responses to Immunotherapy

Abstract

Cancer immunotherapies, such as immune checkpoint blockade or adoptive T cell transfer, can lead to durable responses in the clinic, but response rates remain low due to undefined suppression mechanisms. Solid tumors are characterized by a highly acidic microenvironment that might blunt the effectiveness of anti-tumor immunity. In this study, we directly investigated the effects of tumor acidity on the efficacy immunotherapy. An acidic pH environment blocked T cell activation and limited glycolysis in vitro. IFNγ release blocked by acidic pH did not occur at the level of steady-state mRNA, implying that the effect of acidity was post-translational. Acidification did not affect cytoplasmic pH, such that signals transduced by external acidity were like mediated by specific acid-sensing receptors, four of which are expressed by T cells. Notably, neutralizing tumor acidity with bicarbonate monotherapy impaired the growth of some cancer types in mice where it was associated with increased T cell infiltration. Further, combining bicarbonate therapy with anti-CTLA-4, anti-PD1 or adoptive T cell transfer improved antitumor responses in multiple models, including cures in some subjects. Overall, our findings show how raising intratumoral pH through oral buffers therapy can improve responses to immunotherapy, with the potential for immediate clinical translation.

Cancer cell behaviors mediated by dysregulated pH dynamics at a glance

“…Synergistic inhibition of 3D colony growth and invadopodia formation has been reported in various pancreatic ductal adenocarcinoma (PDAC) cell lines in response to a combination of NHE1 inhibition and erlotinib, an inhibitor of the epidermal growth factor receptor (EGFR) pathway (Cardone et al, 2015). Additionally, based on findings that acidic pH e attenuates immune response (Lardner, 2001), neutralizing pH e has recently been shown to improve responses to cancer immunotherapies (Pilon-Thomas et al, 2016).…”

The acidic microenvironment as a possible niche of dormant tumor cells

“…Inhibition of proton pumps on tumor cells with pantoprazole, another PPI, hampers tumor-induced suppression of macrophages both in vitro and in vivo [94,95]. Finally, neutralization of tumor pH with bicarbonate impairs the growth of cancer in mice, and this effect was associated with an increased T-cell infiltration in tumor masses [96].…”

Phenotypic changes of acid-adapted cancer cells push them toward aggressiveness in their evolution in the tumor microenvironment

“…Acidosis also inhibits anti-tumor immunity and promotes immune editing. 12 From these observations, we have proposed the "acid-mediated invasion" model, wherein tumor-derived acid promotes remodeling of the extracellular matrix, while cancer cells contemporaneously become adapted and more resistant to acidity, compared to the stromal cells into which they invade. 10 However, the mechanism by which tumor cells adapt to this chronic acidosis is not yet fully known.…”