背景:尽管免疫检查点抑制剂(ICIs)彻底改变了癌症治疗领域,只有少数结直肠癌(CRC)患者对此有反应。通过增加主要组织相容性复合物I(MHC-I)表面表达来增强肿瘤免疫原性是增强ICI抗肿瘤功效的有希望的策略。
方法:进行双萤光素酶报告基因测定以发现可增加MHC-I表达的药物候选物。尼罗替尼对MHC-I表达的影响通过双荧光素酶报告基因检测得到证实,qRT-PCR,流式细胞术和蛋白质印迹。通过一系列体外和体内实验评价尼洛替尼的生物学功能。使用RNA-seq分析,免疫荧光测定,西方印迹,流式细胞术,救援实验和微阵列芯片测定,研究了潜在的分子机制。
结果:尼洛替尼诱导CRC细胞中MHC-I表达,在微卫星不稳定性和微卫星稳定模型中,增强CD8+T细胞的细胞毒性,并随后增强抗PDL1的抗肿瘤作用。机械上,尼罗替尼通过cGAS-STING-NF-κB途径促进MHC-ImRNA表达,并通过抑制CRC细胞中PCSK9表达来减少MHC-I降解。PCSK9可以作为CRC的潜在治疗靶点,尼洛替尼可能靶向PCSK9发挥抗CRC作用。
结论:本研究揭示了尼罗替尼通过诱导CRC细胞中MHC-I表达在抗肿瘤免疫中的作用。我们的研究结果表明,尼洛替尼与抗PDL1联合治疗可能是治疗CRC的有效策略。
BACKGROUND: Although immune checkpoint inhibitors (ICIs) have revolutionized the landscape of cancer treatment, only a minority of colorectal cancer (CRC) patients respond to them. Enhancing tumor immunogenicity by increasing major histocompatibility complex I (MHC-I) surface expression is a promising strategy to boost the antitumor efficacy of ICIs.
METHODS: Dual luciferase reporter assays were performed to find drug candidates that can increase MHC-I expression. The effect of nilotinib on MHC-I expression was verified by dual luciferase reporter assays, qRT-PCR, flow cytometry and western blotting. The biological functions of nilotinib were evaluated through a series of in vitro and in vivo experiments. Using RNA-seq analysis, immunofluorescence assays, western blotting, flow cytometry, rescue experiments and microarray chip assays, the underlying molecular mechanisms were investigated.
RESULTS: Nilotinib induces MHC-I expression in CRC cells, enhances CD8+ T-cell cytotoxicity and subsequently enhances the antitumor effects of anti-PDL1 in both microsatellite instability and microsatellite stable models. Mechanistically, nilotinib promotes MHC-I mRNA expression via the cGAS-STING-NF-κB pathway and reduces MHC-I degradation by suppressing PCSK9 expression in CRC cells. PCSK9 may serve as a potential therapeutic target for CRC, with nilotinib potentially targeting PCSK9 to exert anti-CRC effects.
CONCLUSIONS: This study reveals a previously unknown role of nilotinib in antitumor immunity by inducing MHC-I expression in CRC cells. Our findings suggest that combining nilotinib with anti-PDL1 therapy may be an effective strategy for the treatment of CRC.