Targeting KDM4C enhances CD8(+) T cell mediated antitumor immunity by activating chemokine CXCL10 transcription in lung cancer.
Targeting KDM4C enhances CD8(+) T cell mediated antitumor immunity by activating chemokine CXCL10 transcription in lung cancer.
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靶向 KDM4C 通过激活肺癌趋化因子 CXCL10 转录增强 CD8 T 细胞介导的抗肿瘤免疫
DOI：
10.1136/jitc-2021-003716
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发表时间：
2022-03
影响因子：
10.9
通讯作者：
Wu G
中科院分区：
文献类型：
--
作者：
Jie X;Chen Y;Zhao Y;Yang X;Xu Y;Wang J;Meng R;Zhang S;Dong X;Zhang T;Yang K;Xu S;Wu G
尽管免疫检查点阻断（ICB）已被证明在各种肿瘤类型中实现持久的治疗反应，但只有20%-40%的患者从这种治疗中受益。放射治疗（RT）可以增强肿瘤免疫原性，改善ICB反应，但通过结合这两种方式所取得的结果仍然不令人满意的临床。我们先前发现赖氨酸特异性脱甲基酶4C（KDM 4C）是肺癌放射敏感性的调节因子。然而，KDM 4C在抗肿瘤免疫中的作用尚未研究。通过流式细胞术筛选我们的小鼠肿瘤模型中的浸润免疫细胞。建立小鼠体内皮下移植瘤模型和体外条件培养模型，检测CD 8 + T细胞数量和功能的变化。采用RNA测序和染色质免疫沉淀-PCR技术探讨KDM 4C在抗肿瘤免疫中的下游调控机制。开发C57 BL/6小鼠肿瘤模型以评估三联疗法（KDM 4C特异性抑制剂SD 70加RT和抗PD-L1抗体）在体内肺癌中的功效和安全性。KDM 4C的遗传或药理学抑制特异性地增加CD 8 + T细胞浸润;促进CD 8 + T细胞的增殖、迁移和活化;并减轻小鼠肿瘤组织中的CD 8 + T细胞耗竭。在机制上，KDM 4C抑制增加了H3 K36 me 3与CXCL 10启动子区的结合，从而诱导CXCL 10转录并增强CD 8 + T细胞介导的抗肿瘤免疫应答。更重要的是，在所测试的方案中，三联疗法在肺癌中取得了最好的治疗效果且毒性可以耐受。我们的数据揭示了KDM 4C在肺癌抗肿瘤免疫中的关键作用，并表明靶向KDM 4C与放射免疫治疗相结合可能是肺癌中有前途的协同策略。
Although immune checkpoint blockade (ICB) has been proven to achieve a persistent therapeutic response in various tumor types, only 20%–40% of patients benefit from this treatment. Radiotherapy (RT) can enhance tumor immunogenicity and improve the ICB response, but the outcome achieved by combining these two modalities remains clinically unsatisfactory. We previously uncovered that lysine-specific demethylase 4C (KDM4C) is a regulator of radiosensitivity in lung cancer. However, the role of KDM4C in antitumor immunity has not yet been investigated. Infiltrating immune cells in our mouse tumor model were screened by flow cytometry. An in vivo subcutaneous transplanted tumor model and in vitro conditioned culture model were constructed to detect the quantitative and functional changes in CD8+ T cells. RNA sequencing and chromatin immunoprecipitation-PCR assays were used to explore the downstream regulatory mechanism of KDM4C in antitumor immunity. A C57BL/6 mouse tumor model was developed to evaluate the efficacy and safety of a triple therapy (the KDM4C-specific inhibitor SD70 plus RT and an anti-PD-L1 antibody) in lung cancer in vivo. Genetical or pharmacological inhibition of KDM4C specifically increased CD8+ T cell infiltration; promoted the proliferation, migration and activation of CD8+ T cells; and alleviated CD8+ T cell exhaustion in mouse tumor tissues. Mechanistically, KDM4C inhibition increased the binding of H3K36me3 to the CXCL10 promoter region, thus inducing CXCL10 transcription and enhancing the CD8+ T cell mediated antitumor immune response. More importantly, among the tested regimens, the triple therapy achieved the best therapeutic efficacy with tolerable toxicity in lung cancer. Our data reveal a crucial role for KDM4C in antitumor immunity in lung cancer and indicate that targeting KDM4C in combination with radioimmunotherapy might be a promising synergistic strategy in lung cancer.
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