Loss of ATRX suppresses anti-tumor immunity

Alpha-thalassemia/mental retardation syndrome X-linked (ATRX) is a chromatin-modifying enzyme that suffers from loss-of-function in most isocitrate dehydrogenase (IDH)-mutant astrocytomas.ATRX has long been recognized as a chaperone for histone core H3.3, a variant associated with heterochromatin and enriched in telomeres. 1ATRX mutations correlate with telomere lengthening via the alternative lengthening of telomeres (ALT) pathway in several cancers, where it appears ATRX loss is necessary but not sufficient for ALT. 2 ATRX loss also inhibits DNA-damage repair, 3 as H3.3 likewise plays a role during strand synthesis.However, while histone H3.3 is also deposited throughout the genome, 4 less is known about the impact of ATRX mutations on gene expression.In this issue, Hu et al 5 show that ATRX knockdown (KD) induces an immunosuppressive gene expression program in IDH-mutant glioma, including the upregulation of the immune-checkpoint programmed death-ligand 1 (PD-L1) and the secretion of immunosuppressive cytokines.Cytokine expression in ATRX-KD gliomas was further enhanced by chemo-radiation.ATRX-KD cells were more resistant to T-cell killing in vitro and induced T-cell apoptosis at significantly higher rates than controls.These effects could be abrogated, however, by pre-treatment with anti-PD-L1 antibodies.Likewise, elaborated contact with ATRX-KD cells polarized macrophages toward an M2 expression program.Macrophages treated with conditioned media from ATRX-KD cells inhibited T-cell proliferation.In vivo, ATRX-KD gliomas continued to over-express PD-L1 and the immunosuppressive cytokines observed in vitro.Orthotopic ATRX-KD tumors were more heavily infiltrated by macrophages.Moreover, macrophages in ATRX-KD tumors expressed higher levels of arginase and immunosuppressive cytokines.PD-L1 and cytokine expression could be regressed in ATRX-KD gliomas by targeting bromo-and extra-terminal (BET) family proteins, epigenetic readers of acetylated lysine residues.This suggests that whatever chromatin remodeling is induced by ATRX-KD, it leads to increased activity of DNA enhancers of PD-L1 and specific immunosuppressive cytokines.These results dovetail with recent findings from our laboratory and others which show that ATRX loss in glioma, 6 Overall survival