PHF8 enables immune evasion by silencing endogenous retroelements [ATAC-seq]

Immunotherapy is currently a prime approach to cancer treatment. Despite the promise of immunotherapies such as immune checkpoint blockade on multiple cancers, most patients do not have a response or become resistant to treatment. Recent work indicate that epigenetic therapies converge with cancer immunotherapy through ‘viral mimicry’, the antiviral response triggered by endogenous nuclei acids that derived from aberrantly transcribed endogenous retrotransposons. However, epigenetic factors that regulate endogenous retrotransposons and further modulate the immune sensitivity of tumor cells is largely unknown. Here we identified the histone demethylase PHD finger protein 8 (PHF8, KDM7B), a Jumonji C domain-containing protein that erases repressive histone marks as an essential mediator of immune escape. We found that depletion of PHF8 abrogates tumor growth, induces immune memory and augments sensitivity to immune checkpoint blockade in multiple tumor models without directly affecting tumor cell proliferation. ATAC-seq data for CT26 control (n=2), Phf8 KO (n=2), or IFNγ-treated CT26 control (n=2), Phf8 KO (n=2) cells.

免疫疗法目前是癌症治疗的核心手段之一。尽管免疫检查点阻断（immune checkpoint blockade）等免疫疗法在多种癌症中展现出应用潜力，但多数患者仍未产生应答或出现治疗耐药性。近期研究表明，表观遗传疗法（epigenetic therapies）可通过‘病毒模拟’（viral mimicry）机制与癌症免疫疗法产生协同作用——即由异常转录的内源性逆转录转座子（endogenous retrotransposons）衍生的内源性核酸触发的抗病毒应答。然而，目前学界对调控内源性逆转录转座子、进而调节肿瘤细胞免疫敏感性的表观遗传因子仍知之甚少。本研究鉴定出组蛋白去甲基化酶（histone demethylase）PHD指蛋白8（PHD finger protein 8，PHF8, KDM7B）——一种可清除抑制性组蛋白修饰（repressive histone marks）的含Jumonji C结构域（Jumonji C domain）蛋白——作为免疫逃逸（immune escape）的关键介导因子。研究发现，敲除PHF8可抑制肿瘤生长、诱导免疫记忆（immune memory），并在多种肿瘤模型中增强对免疫检查点阻断疗法的敏感性，且不会直接影响肿瘤细胞的增殖活性。本研究获取了CT26对照细胞（n=2）、Phf8基因敲除细胞（n=2），以及经干扰素γ（IFNγ）处理的CT26对照细胞（n=2）、Phf8基因敲除细胞（n=2）的转座酶可及性染色质测序（ATAC-seq）数据。