Extracellular pH modulating injectable gel for enhancing immune checkpoint inhibitor therapy.

ABSTRACT

Clinical data from diverse cancer types shows that the increased T cell infiltration in tumors correlates with improved patient prognosis. Acidic extracellular pH is a major attribute of the tumor microenvironment (TME) that promotes immune evasion and tumor progression. Therefore, antagonizing tumor acidity can be a powerful approach in cancer immunotherapy. Here, Pluronic F-127 is used as a NaHCO3 releasing carrier to focally alleviate extracellular tumor acidity. In a mouse tumor model, intratumoral treatment with pH modulating injectable gel (pHe-MIG) generates immune-favorable TME, as evidenced by the decrease of immune-suppressive cells and increase of tumor infiltrating CD8+T cells. The combination of pHe-MIG with immune checkpoint inhibitors, anti-PD-1 and anti-TIGIT antibodies, increases intratumoral T cell function, which leads to tumor clearance. Mechanistically, extracellular acidity was shown to upregulate co-inhibitory immune checkpoint receptors and inhibit mTOR signaling pathways in memory CD8+T cells, which impaired effector functions. Furthermore, an acidic pH environment increased the expression and engagement of TIGIT and its ligand CD155, which suggested that the extracellular pH can regulate the suppressive function of TIGIT pathway. Collectively, these findings suggest that pHe-MIG holds potential as a new TME modulator for effective immune checkpoint inhibitor therapies.