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

Abstract

Although immune checkpoint blockade (ICB) therapy has revolutionized cancer treatment, many patients do not respond or develop resistance to ICB. N6-methylation of adenosine (m6A) in RNA regulates many pathophysiological processes. Here, we show that deletion of the m6A demethylase Alkbh5 sensitized tumors to cancer immunotherapy. Alkbh5 has effects on m6A 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 m6A 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.

The m6A RNA Demethylase ALKBH5 Promotes Radioresistance and Invasion Capability of Glioma Stem Cells

“…R-2-hydroxyglutarate (R-2HG), an oncometabolite resulting from the conversion of α-ketoglutarate by mutant IDH1/2 enzymes, has also been shown to specifically inhibit FTO and proliferation of leukemic or GBM cells [ 13 ]. More recently, a study also reported the efficacy of a specific ALKBH5 inhibitor, ALK04, in reducing tumor growth of melanoma cells [ 57 ]. Several other compounds, including (rhein, MO-I-500, Entacapone, NCDPCB, CHTB), have also been described as FTO or ALKBH5 potential inhibitors, although their anti-tumoral action has not been demonstrated [ 58 ].…”

Role of Methylation in Pro- and Anti-Cancer Immunity

“…Furthermore, KD of FTO sensitized melanoma cells to IFNγ, thereby reducing resistance to anti-PD-1 therapy. Similarly, RNA demethylase ALKBH5 KO showed significant reduction in tumor growth and prolonged mouse survival during ICPi therapy in B16 melanoma and CT26 colon cancer mouse models [ 183 ]. This was due to ALKBH5 altering gene expression and splicing that leads to changes in lactate levels in the TME.…”

Glycolysis-induced drug resistance in tumors—A response to danger signals?

“…Strikingly, many different classes of antitumor drugs have been found being associated with glycolysis-induced resistance: a large number of different chemotherapeutics [15] , [16] , [17] , [18] , [19] , [20] , [21] , [22] , [23] , large molecule therapeutics like monoclonal antibodies (mAb) targeting a variety of different antigens, including immune checkpoint inhibitors [1 , [24] , [25] , [26] , [27] , [28] , [29] , [30] , [31] , hormone antagonists [1 , 32] , targeted, small molecule therapeutics like tyrosine kinase inhibitors (TKI) [1 , [33] , [34] , [35] , [36] , glucocorticoids [1 , 37] , and ionizing radiation [1 , 38] . While the mechanisms underlying glycolysis-induced drug resistance will be discussed in a later section, it can be anticipated that the broad range of therapeutic agents associated with glycolysis-induced resistance, spanning from small molecule drugs to large-sized molecules like mAbs, likely involves different mechanisms that may vary according to the different classes of molecules.…”