肿瘤细胞治疗研究
英文原题：Targeting TBK1 potentiates oncolytic virotherapy via amplifying ICAM1-mediated NK cell immunity in chemo-resistant colorectal cancer.
本研究通过联合溶瘤病毒（OVs）与 TBK1 抑制剂（TBK1i），提出了一种治疗化疗耐药结直肠癌（CRC）的有前景的方法。
背景：肿瘤耐药是癌症患者治疗失败的主要原因。溶瘤病毒（OV）作为一种新疗法，正快速进入临床评估，通常在对标准化疗耐药的复发肿瘤中进行研究。然而，促进化疗耐药的适应过程是否会影响OV疗效尚不清楚。方法：利用体外、体内和患者来源类器官模型分析化疗耐药结直肠癌（CRC）对OV的敏感性。通过RNA测序分析和临床样本免疫组织化学检测TANK结合激酶1（TBK1）表达。采用单细胞RNA测序、流式细胞术和体内中和实验，证明TBK1抑制剂（TBK1i）与OV联合可重编程肿瘤免疫微环境，尤其是活化自然杀伤（NK）细胞。RNA测序分析确定细胞间黏附分子1（ICAM-1）可能是NK细胞活化的关键靶点，随后通过体内外挽救实验验证ICAM-1对NK细胞活性的影响。结果：化疗耐药CRC在体外、体内及患者来源类器官中对OV的敏感性均降低。进一步研究发现，化疗耐药CRC中TBK1异常活化，介导I型干扰素通路活化并损害病毒复制。抑制TBK1可增强肿瘤内病毒复制及体外直接溶瘤作用，并增强OV在体内诱导的抗肿瘤免疫。免疫细胞谱显示，OV/TBK1i联合重塑肿瘤微环境，尤其活化NK细胞应答。免疫细胞清除实验表明，NK细胞是OV/TBK1i协同治疗活性所必需的。从机制上看，TBK1抑制与VSV 51协同，以RIPK1依赖方式上调ICAM1表达，促进NK细胞介导的肿瘤杀伤。结论：本研究提出一种治疗化疗耐药CRC的有前景方法，即联合使用OV和TBK1抑制剂。
BACKGROUND: Tumor resistance is the primary reason for treatment failure in patients with cancer, while oncolytic viruses (OVs), as a novel therapy, have been rapidly advancing through clinical evaluation and are typically assessed in recurrent tumors that are refractory to standard chemotherapy. However, whether the adaptive process that fosters chemotherapy resistance influences the efficacy of OV therapy is unknown. METHODS: We analyzed chemo-resistant colorectal cancer (CRC) using in vitro, in vivo, and patient-derived organoid models to assess sensitivity to OVs. Through RNA sequencing analysis and immunohistochemistry were performed in clinical samples that indicated TANK-binding kinase 1 (TBK1) expression. Using single-cell RNA sequencing, flow cytometry, and in vivo neutralization assays to demonstrate that the combination of TBK1 inhibitor (TBK1i) and OVs reprograms the tumor immune microenvironment, particularly by activating natural killer (NK) cells. Through RNA sequencing analysis, we identified intercellular cell adhesion molecule-1 (ICAM-1) as a potential target responsible for NK cell activation. Subsequently, we designed and conducted rescue experiments, both in vitro and in vivo, to validate the influence of ICAM-1 on NK cell activity. RESULTS: We demonstrated that chemo-resistant CRC showed decreased sensitivity to the OV in vitro, in vivo, and patient-derived organoids. Further investigation revealed aberrant activation of TBK1 in chemo-resistant CRC, which mediated the activation of the type I interferon pathway and impaired viral replication. TBK1 inhibition enhanced intratumor viral replication and direct oncolysis effect in vitro and augmented the antitumor immunity elicited by OVs in vivo. Immune cell profiles presented that OV/TBK1i combination reshaped the tumor microenvironment and especially activated the NK cell response. Immune cell depletion studies demonstrated that NK cells were required for the synergistic therapeutic activity of the OV/TBK1i combination. Mechanistically, TBK1 inhibition synergized with VSV 51 to increase ICAM1 expression in a RIPK1-dependent manner, promoting NK cell-mediated tumor killing. CONCLUSION: This study presents a promising approach for treating chemo-resistant CRC by combining OVs and TBK1i.
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