PHF8 enables immune evasion by silencing endogenous retroelements [CHIP-seq]. PHF8 enables immune evasion by silencing endogenous retroelements [CHIP-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. Overall design: Chromatin immunoprecipitation DNA-sequencing (ChIP-seq) for H3K9me1, H3K9me2, H3K9me3, H3K27me2 and H4K20me1 in CT26 control and Phf8 KO cells.

免疫疗法当前已是癌症治疗的首要策略。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，但多数患者仍无法产生响应，或最终产生治疗耐药性。近期研究表明，表观遗传疗法可通过‘病毒模拟（viral mimicry）’途径与癌症免疫疗法产生协同效应——该途径指由异常转录的内源性逆转录转座子衍生的内源性核酸所触发的抗病毒应答。然而，目前对于调控内源性逆转录转座子并进一步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PHD指蛋白8（PHF8, KDM7B），该蛋白属于含有Jumonji C结构域（Jumonji C domain）的蛋白家族，可清除抑制性组蛋白修饰，是免疫逃逸的关键介导因子。研究发现，敲除PHF8可抑制肿瘤生长、诱导免疫记忆，并在多种肿瘤模型中增强对免疫检查点阻断的敏感性，且不会直接影响肿瘤细胞的增殖能力。实验整体设计：在CT26野生型细胞与Phf8敲除（KO）细胞中，针对H3K9me1、H3K9me2、H3K9me3、H3K27me2及H4K20me1开展染色质免疫沉淀测序（ChIP-seq）。