Many colorectal cancer (CRC) patients do not respond to immune checkpoint blockade (ICB) therapy, highlighting the urgent need to understand tumor resistance mechanisms. Recently, the link between the IFNγ signaling pathway integrity and ICB resistance in the CRC tumor microenvironment has been revealed. The immunosuppressive microenvironment poses a significant challenge to antitumor immunity in CRC development. Tumor-associated neutrophils (TANs) found in tumor tissues exhibit an immunosuppressive phenotype and are associated with CRC patient prognosis. Neutrophil extracellular traps (NETs), DNA meshes containing cytotoxic enzymes released into the extracellular space, may be promising therapeutic targets in cancer. This study showed increased NETs in tumor tissues and peripheral neutrophils of high levels of microsatellite instability (MSI-H) CRC patients compared to microsatellite stable (MSS) CRC patients. IFNγ response genes were enriched in MSI-H CRC patients compared to MSS CRC patients. Co-culturing neutrophils with MSI-H CRC cell lines induced more NET formation and higher cellular apoptosis than MSS CRC cell lines. IFNγ treatment induced more NET formation and apoptosis in MSS CRC cell lines. Using subcutaneous or orthotopic CT-26 (MSS)-tumor-bearing mice models, IFNγ reduced tumor size and enhanced PD-1 antibody-induced tumor-killing activity, accompanied by upregulated NETs and cellular apoptosis. These findings suggest IFNγ could be a therapeutic strategy for MSS CRC.

中文翻译：

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干扰素γ诱导更高的中性粒细胞胞外陷阱，从而在微卫星稳定结直肠癌中产生肿瘤杀伤活性

许多结直肠癌（CRC）患者对免疫检查点阻断（ICB）治疗没有反应，这凸显了了解肿瘤耐药机制的迫切需要。最近，CRC 肿瘤微环境中 IFNγ 信号通路完整性与 ICB 耐药性之间的联系已被揭示。免疫抑制微环境对结直肠癌发展中的抗肿瘤免疫提出了重大挑战。肿瘤组织中发现的肿瘤相关中性粒细胞 (TAN) 表现出免疫抑制表型，与 CRC 患者预后相关。中性粒细胞胞外陷阱 (NET) 是一种含有释放到细胞外空间的细胞毒性酶的 DNA 网，可能是癌症的有希望的治疗靶点。这项研究表明，与微卫星稳定 (MSS) CRC 患者相比，高水平微卫星不稳定 (MSI-H) CRC 患者的肿瘤组织和外周中性粒细胞中的 NET 有所增加。与 MSS CRC 患者相比，MSI-H CRC 患者的 IFNγ 反应基因丰富。与 MSS CRC 细胞系相比，中性粒细胞与 MSI-H CRC 细胞系共培养可诱导更多 NET 形成和更高的细胞凋亡。IFNγ处理诱导MSS CRC细胞系中更多的NET形成和细胞凋亡。使用皮下或原位 CT-26 (MSS) 荷瘤小鼠模型，IFNγ 缩小了肿瘤大小，增强了 PD-1 抗体诱导的肿瘤杀伤活性，同时上调了 NET 和细胞凋亡。这些发现表明 IFNγ 可能是 MSS CRC 的一种治疗策略。