Xun Jing, Liu Zehan, Liu Bin, Jiang Xiaolin, Yang Huichao, Liu Jinjin, Wang Botao, Gao Ruifang, Zhang Aimin, Wu Xueliang, Xi Qing, Yu Xiangyang, Zhang Qi
Tianjin Nankai Hospital, Tianjin Medical University, Tianjin 300100, China.
Institute of Integrative Medicine for Acute Abdominal Diseases, Tianjin 300100, China.
J Cancer. 2025 Jul 28;16(12):3629-3642. doi: 10.7150/jca.118571. eCollection 2025.
Cytotoxic CD8 T cells play a vital role in its antitumor response, and increasing their infiltration in tumors is an effective strategy for enhancing the efficacy of antitumor immunotherapy. Lysine-specific demethylase 6B (KDM6B) plays a suppressive or oncogenic role in colorectal cancer (CRC). However, the its contribution in CRC immunity remains unclear. The expression of KDM6B was analyzed in CRC using TCGA database and clinical specimens. Its role in tumor growth and metastasis was assessed through in vitro assays and in vivo models, including subcutaneous xenografts and orthotopic liver metastasis mice. CD8 T cell infiltration, recruitment, and activation were assessed via immunohistochemistry, transwell assay, and flow cytometry. The expression of PD-L1 and CD8 T cell-recruiting chemokines CCL5, CXCL9, CXCL10 were detected. GSEA identified KDM6B-regulated signaling pathways. ChIP‒qPCR was used to determined the enrichment level of H3K27me3 on PD-L1, CCL5, CXCL9, and CXCL10 promoters. Finally, the synergistic effect of KDM6B inducer paricalcitol with anti-PD-L1 therapy was investigated using a subcutaneous xenograft mouse model. KDM6B was downregulated in CRC tissues and cells. KDM6B overexpression suppressed CRC proliferation, tumor growth and liver metastasis, while enhancing CD8 T cells infiltration, recruitment, and functional activation. KDM6B upregulated PD-L1 and CCL5, CXCL9, CXCL1 expression in CRC cells. Mechanically, GSEA revealed JAK/STAT pathway enrichment. KDM6B increased p-STAT3 levels and the STAT3 signaling mediated the promoting effect of KDM6B on PD-L1 and chemokines expression. In addition, KDM6B overexpression reduced H3K27me3 enrichment on promoters of PD-L1 and chemokines. Finally, the combination of paricalcitol and anti-PD-L1 antibody enhanced anti-tumor efficacy in CRC mouse model. KDM6B potentially suppresses CRC progression by enhancing CD8 T cell infiltration via dual mechanisms: STAT3-mediated transcriptional activation and H3K27me3 demethylase-dependent epigenetic remodeling of PD-L1 and chemokine genes (CCL5/CXCL9/CXCL10). The synergistic effect of KDM6B inducer paricalcitol with anti-PD-L1 enhances antitumor immunity, supporting its potential combination strategy for CRC treatment.
细胞毒性CD8 T细胞在其抗肿瘤反应中起着至关重要的作用，增加它们在肿瘤中的浸润是提高抗肿瘤免疫治疗疗效的有效策略。赖氨酸特异性去甲基化酶6B（KDM6B）在结直肠癌（CRC）中发挥抑制或致癌作用。然而，其在CRC免疫中的作用仍不清楚。使用TCGA数据库和临床标本分析了CRC中KDM6B的表达。通过体外试验和体内模型，包括皮下异种移植和原位肝转移小鼠，评估了其在肿瘤生长和转移中的作用。通过免疫组织化学、Transwell试验和流式细胞术评估CD8 T细胞的浸润、募集和激活。检测了PD-L1和CD8 T细胞募集趋化因子CCL5、CXCL9、CXCL10的表达。基因集富集分析（GSEA）确定了KDM6B调节的信号通路。染色质免疫沉淀-定量聚合酶链反应（ChIP-qPCR）用于确定H3K27me3在PD-L1、CCL5、CXCL9和CXCL10启动子上的富集水平。最后，使用皮下异种移植小鼠模型研究了KDM6B诱导剂帕立骨化醇与抗PD-L1治疗的协同作用。KDM6B在CRC组织和细胞中表达下调。KDM6B过表达抑制CRC增殖、肿瘤生长和肝转移，同时增强CD8 T细胞浸润、募集和功能激活。KDM6B上调CRC细胞中PD-L1和CCL5、CXCL9、CXCL1的表达。机制上，GSEA显示JAK/STAT通路富集。KDM6B增加p-STAT3水平，STAT3信号介导KDM6B对PD-L1和趋化因子表达的促进作用。此外，KDM6B过表达降低了PD-L1和趋化因子启动子上H3K27me3的富集。最后，帕立骨化醇和抗PD-L1抗体的联合使用增强了CRC小鼠模型的抗肿瘤疗效。KDM6B可能通过双重机制增强CD8 T细胞浸润来抑制CRC进展：STAT3介导的转录激活以及PD-L1和趋化因子基因（CCL5/CXCL9/CXCL10）的H3K27me3去甲基化酶依赖性表观遗传重塑。KDM6B诱导剂帕立骨化醇与抗PD-L1的协同作用增强了抗肿瘤免疫力，支持其作为CRC治疗的潜在联合策略。
