산성 종양 미세환경 조절을 통한 항암면역 증진에 대한 연구

Abstract

The tumor microenvironment (TME) is a complex environment where cancer cells reside and interact with different types of cells, including immune cells. The TME has been known to be a critical facilitator of immune escape and cancer progression. 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 TME, mainly due to the high aerobic and glycolytic rate of tumor cells. The acidic TME has been reported to promote immune evasion and tumor progression. Therefore, antagonizing tumor acidity can be a powerful approach in cancer immunotherapy. Herein, the effect of tumor acidity on the efficacy of immunotherapy was investigated. An acidic pH environment suppressed antigen-specific memory CD8+ T cell responses in vitro. 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. A NaHCO₃ loaded thermosensitive hydrogel (pH modulating injectable gel (pHe-MIG)) was employed to focally neutralize extracellular pH of the TME. Normalization of the acidic TME by intratumoral pHe-MIG injection transformed the immune-suppressive TME into an immune-favorable condition, as evidenced by the decrease of immune-suppressive cells and increase of tumor infiltrating CD8+ T cells. Furthermore, the intratumoral CD8+ T cells exhibited enhanced cytolytic activity with a less exhausted profile. The combination of pHe-MIG with a low dose of immune checkpoint inhibitors, anti-PD-1 and anti-TIGIT antibodies, improved intratumoral cytotoxic T cell function and tumor clearance. Collectively, these findings suggest that pHe-MIG holds potential as a new TME modulator for effective immune checkpoint inhibitor therapies.