Xu Ning, Qiu Huisi, Sun Yuezhang, Jin Hong, Yan Siyu, Zhang Fangmei, Song Ying, Zheng Guopei, Liao Dongjiang, Wei Xiaoli, Luo Liyun
Guangzhou Institute of Cancer Research, the Affiliated Cancer Hospital, Guangzhou Medical University, Guangzhou, Guangdong, China.
The Affiliated Qingyuan Hospital (Qingyuan People's Hospital), Guangzhou Medical University, Qingyuan, Guangdong, China.
J Immunother Cancer. 2025 Sep 15;13(9):e011766. doi: 10.1136/jitc-2025-011766.
Distant metastasis and immune evasion are the major obstacles for successful colorectal cancer (CRC) treatment. The link between metastasis and immune evasion, as well as their therapeutic significance, remains unclear.
Long non-coding RNAs from six paired CRC and normal tissues were screened by RNA sequencing (RNA-seq). LncRNA-CTD (CTD-2568A17.8) expression levels were determined using in situ hybridization and quantitative PCR analysis. In vitro and in vivo assays were performed to confirm the function of lncRNA-CTD. Flow cytometry was used to analyze the impact of lncRNA-CTD on immune cell infiltration and T-cell function. RNA-seq combined with RNA pull-down and RNA immunoprecipitation assay was used to identify the changes in downstream molecules induced by lncRNA-CTD. The therapeutic value of the combination of lncRNA-CTD and immune checkpoint inhibitors has been evaluated.
In this study, we identified a novel long non-coding RNA, lncRNA-CTD, which is downregulated in CRC and correlates with both metastasis and immunotherapy response. Mechanistically, the interaction of lncRNA and smad2 prevented the phosphorylation and nuclear translocation of smad2, which inhibited the expression of snail1, thereby inhibiting the metastasis of CRC. LncRNA-CTD enhances major histocompatibility complex class I (MHC-I) expression on the cancer cell membrane by interacting with STUB1 to disrupt the interaction of STUB1 with the MHC-I activator NLRC5 and subsequent NLRC5 ubiquitination-mediated degradation, increasing the susceptibility of CRC cells to being killed by CD8 T cells. TFAP4 overexpression in CRC cells caused lncRNA-CTD downregulation. Moreover, the combination of lncRNA-CTD gene delivery therapy with immune checkpoint inhibitors exerted an additive effect on tumor growth inhibition.
Collectively, our study reveals the role and mechanism of lncRNA-CTD in CRC metastasis and immune evasion. Overexpression of lncRNA-CTD suppresses CRC metastasis and improves the efficacy of immune checkpoint inhibitors.Cite Now.
远处转移和免疫逃逸是结直肠癌（CRC）治疗成功的主要障碍。转移与免疫逃逸之间的联系及其治疗意义仍不清楚。
通过RNA测序（RNA-seq）筛选来自六对CRC组织和正常组织的长链非编码RNA。使用原位杂交和定量PCR分析确定LncRNA-CTD（CTD-2568A17.8）的表达水平。进行体外和体内实验以证实lncRNA-CTD的功能。流式细胞术用于分析lncRNA-CTD对免疫细胞浸润和T细胞功能的影响。RNA-seq结合RNA下拉和RNA免疫沉淀实验用于鉴定由lncRNA-CTD诱导的下游分子的变化。评估了lncRNA-CTD与免疫检查点抑制剂联合使用的治疗价值。
在本研究中，我们鉴定了一种新型长链非编码RNA，lncRNA-CTD，其在CRC中表达下调，并且与转移和免疫治疗反应相关。机制上，lncRNA与smad2的相互作用阻止了smad2的磷酸化和核转位，从而抑制了snail1的表达，进而抑制了CRC的转移。LncRNA-CTD通过与STUB1相互作用增强癌细胞膜上主要组织相容性复合体I类（MHC-I）的表达，破坏STUB1与MHC-I激活剂NLRC5的相互作用以及随后NLRC5泛素化介导的降解，增加CRC细胞被CD8 T细胞杀伤的敏感性。CRC细胞中TFAP4的过表达导致lncRNA-CTD下调。此外，lncRNA-CTD基因递送疗法与免疫检查点抑制剂联合使用对肿瘤生长抑制具有相加作用。
总体而言，我们的研究揭示了lncRNA-CTD在CRC转移和免疫逃逸中的作用及机制。lncRNA-CTD的过表达抑制CRC转移并提高免疫检查点抑制剂的疗效。立即引用。
