ALKBH5 regulates anti–PD-1 therapy response by modulating lactate and suppressive immune cell accumulation in tumor microenvironment

Significance

N ⁶ -methylation of adenosine (m ⁶A) RNA modification plays important roles in development and tumorigenesis. The functions and mechanisms of m ⁶A demethylases during cancer immunotherapy is still unclear. Here we employed melanoma and colon syngeneic mouse models to study the roles of m ⁶A demethylases ALKBH5 and FTO during anti–PD-1 antibody and GVAX vaccination therapy. We found that ALKBH5 knockout in tumor cells enhances efficacy of immunotherapy and prolonged mouse survival. ALKBH5 modulates target gene expression and gene splicing, leading to changes of metabolite contents, such as lactate in tumor microenvironment, which regulates suppressive lymphocytes Treg and myeloid-derived suppressor cell accumulations. Importantly, by using ALKBH5-specific inhibitor, we observed the similar phenotype, indicating future translational application of our findings.

Abstract

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N ⁶ -methylation of adenosine (m ⁶A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m ⁶A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m ⁶A density and splicing events in tumors during ICB. Alkbh5 modulates Mct4/Slc16a3 expression and lactate content of the tumor microenvironment and the composition of tumor-infiltrating Treg and myeloid-derived suppressor cells. Importantly, a small-molecule Alkbh5 inhibitor enhanced the efficacy of cancer immunotherapy. Notably, the ALKBH5 gene mutation and expression status of melanoma patients correlate with their response to immunotherapy. Our results suggest that m ⁶A demethylases in tumor cells contribute to the efficacy of immunotherapy and identify ALKBH5 as a potential therapeutic target to enhance immunotherapy outcome in melanoma, colorectal, and potentially other cancers.