T细胞在对IL1和TNFα炎症有反应的肿瘤中指导免疫检查点抑制剂治疗耐药性。
T Cells Instruct Immune Checkpoint Inhibitor Therapy Resistance in Tumors Responsive to IL1 and TNFα Inflammation.
作者信息
Cho Nam Woo, Guldberg Sophia M, Nabet Barzin Y, Yu Jie Zeng, Kim Eun Ji, Hiam-Galvez Kamir J, Yee Jacqueline L, DeBarge Rachel, Tenvooren Iliana, Ashitey Naa Asheley, Lynce Filipa, Dillon Deborah A, Rosenbluth Jennifer M, Spitzer Matthew H
机构信息
Department of Radiation Oncology, University of California, San Francisco, San Francisco, California.
Department of Otolaryngology - Head and Neck Surgery, University of California, San Francisco, San Francisco, California.
出版信息
Cancer Immunol Res. 2025 Feb 3;13(2):229-244. doi: 10.1158/2326-6066.CIR-24-0416.
Resistance to immune checkpoint inhibitors (ICI) is common, even in tumors with T-cell infiltration. We thus investigated consequences of ICI-induced T-cell infiltration in the microenvironment of resistant tumors. T cells and neutrophil numbers increased in ICI-resistant tumors following treatment, in contrast to ICI-responsive tumors. Resistant tumors were distinguished by high expression of IL1 receptor 1, enabling a synergistic response to IL1 and TNFα to induce G-CSF, CXCL1, and CXCL2 via NF-κB signaling, supporting immunosuppressive neutrophil accumulation in tumor. Perturbation of this inflammatory resistance circuit sensitized tumors to ICIs. Paradoxically, T cells drove this resistance circuit via TNFα both in vitro and in vivo. Evidence of this inflammatory resistance circuit and its impact also translated to human cancers. These data support a mechanism of ICI resistance, wherein treatment-induced T-cell activity can drive resistance in tumors responsive to IL1 and TNFα, with important therapeutic implications.
即使在有T细胞浸润的肿瘤中，对免疫检查点抑制剂（ICI）产生耐药也很常见。因此，我们研究了ICI诱导的T细胞浸润在耐药肿瘤微环境中的后果。与ICI敏感肿瘤相反，治疗后ICI耐药肿瘤中的T细胞和中性粒细胞数量增加。耐药肿瘤的特征是白细胞介素1受体1（IL1 receptor 1）高表达，这使得肿瘤对IL1和肿瘤坏死因子α（TNFα）产生协同反应，通过核因子κB（NF-κB）信号传导诱导粒细胞集落刺激因子（G-CSF）、CXC趋化因子配体1（CXCL1）和CXC趋化因子配体2（CXCL2），从而支持免疫抑制性中性粒细胞在肿瘤中积聚。破坏这种炎症抗性回路可使肿瘤对ICI敏感。矛盾的是，T细胞在体外和体内均通过TNFα驱动这一抗性回路。这种炎症抗性回路及其影响的证据也适用于人类癌症。这些数据支持了一种ICI耐药机制，即治疗诱导的T细胞活性可在对IL1和TNFα有反应的肿瘤中驱动耐药，具有重要的治疗意义。
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