CBX4 promotes antitumor immunity by suppressing Pdcd1 expression in T cells

Abstract

E3 SUMO‐protein ligase CBX4 (CBX4), a key component of polycomb‐repressive complexes 1 (PRC1), has been reported to regulate a variety of genes implicated in tumor growth, metastasis, and angiogenesis. However, its role in T‐cell‐mediated antitumor immunity remains elusive. To shed light on this issue, we generated mice with T‐cell‐specific deletion of Cbx4. Tumor growth was increased in the knockout mice. Additionally, their tumor‐infiltrating lymphocytes exhibited impaired tumor necrosis factor‐alpha (TNF‐α) and interferon‐gamma (IFN‐γ) production, with an elevated programmed cell death protein 1 (PD‐1) level. In fact, dysregulated Pdcd1 expression was observed in all major subsets of peripheral T cells from the knockout mice, which was accompanied by a functional defect in response to T‐cell receptor (TCR) stimulation. In support of a direct link between CBX4 and PD‐1, Cbx4 overexpression resulted in the downregulation of Pdcd1 expression. Epigenetic analyses indicated that Cbx4 deficiency leads to diminished accumulation of inhibitory histone modifications at conserved region (CR)‐C and CR‐B sites of the Pdcd1 promoter, namely mono‐ubiquitinated histone H2A at lysine 119 (H2AK119ub1) and trimethylated histone H3 at lysine 27 (H3K27me3). Moreover, inhibition of either the E3 ligase activity of polycomb‐repressive complexes 1 (PRC1) or the methyltransferase activity of polycomb‐repressive complexes 2 (PRC2) restores Pdcd1 expression in Cbx4‐transfected cells. Cumulatively, this study reveals a novel function of CBX4 in the regulation of T‐cell function and expands our understanding of the epigenetic control of Pdcd1 expression.