小柯机器人

美国密歇根大学Weiping Zou、Michael D. Green等研究人员合作发现，肝转移通过巨噬细胞介导的T细胞消除来抑制免疫疗法。相关论文于2021年1月4日在线发表在《自然—医学》杂志上。

研究人员发现，肝转移系统地降低了患者和临床前模型的免疫治疗效果。肝转移患者从免疫治疗中获得的获益有限，而与其他已建立的反应生物标志物无关。在多个小鼠模型中，研究人员显示肝转移灶从系统循环中吸出激活的CD8⁺T细胞。在肝脏中，活化的抗原特异性Fas⁺CD8⁺T细胞在与FasL⁺CD11b⁺F4/80⁺单核细胞衍生的巨噬细胞相互作用后经历凋亡。因此，在临床前模型中，肝转移会形成全身性免疫荒漠。同样，患有肝转移的患者外周血T细胞数量减少，肿瘤T细胞多样性和功能降低。

在临床前模型中，肝定向放射治疗消除了免疫抑制性肝巨噬细胞，增加了肝T细胞存活率并减少了肝对T细胞的虹吸。因此，肝转移选择宿主外周耐受机制，通过CD8⁺T细胞缺失引起获得性免疫治疗抗性，并且肝定向放疗和免疫治疗的结合可以促进全身性抗肿瘤免疫。

据悉，转移是癌症死亡的主要原因，并且癌症经常转移到肝脏。尚不清楚肝脏免疫耐受机制是否有助于癌症结果。

附：英文原文

Title: Liver metastasis restrains immunotherapy efficacy via macrophage-mediated T cell elimination

Author: Jiali Yu, Michael D. Green, Shasha Li, Yilun Sun, Sara N. Journey, Jae Eun Choi, Syed Monem Rizvi, Angel Qin, Jessica J. Waninger, Xueting Lang, Zoey Chopra, Issam El Naqa, Jiajia Zhou, Yingjie Bian, Long Jiang, Alangoya Tezel, Jeremy Skvarce, Rohan K. Achar, Merna Sitto, Benjamin S. Rosen, Fengyun Su, Sathiya P. Narayanan, Xuhong Cao, Shuang Wei, Wojciech Szeliga, Linda Vatan, Charles Mayo, Meredith A. Morgan, Caitlin A. Schonewolf, Kyle Cuneo, Ilona Kryczek, Vincent T. Ma, Christopher D. Lao, Theodore S. Lawrence, Nithya Ramnath, Fei Wen, Arul M. Chinnaiyan, Marcin Cieslik, Ajjai Alva, Weiping Zou

Issue&Volume: 2021-01-04

Abstract: Metastasis is the primary cause of cancer mortality, and cancer frequently metastasizes to the liver. It is not clear whether liver immune tolerance mechanisms contribute to cancer outcomes. We report that liver metastases diminish immunotherapy efficacy systemically in patients and preclinical models. Patients with liver metastases derive limited benefit from immunotherapy independent of other established biomarkers of response. In multiple mouse models, we show that liver metastases siphon activated CD8+ T cells from systemic circulation. Within the liver, activated antigen-specific Fas+CD8+ T cells undergo apoptosis following their interaction with FasL+CD11b+F4/80+ monocyte-derived macrophages. Consequently, liver metastases create a systemic immune desert in preclinical models. Similarly, patients with liver metastases have reduced peripheral T cell numbers and diminished tumoral T cell diversity and function. In preclinical models, liver-directed radiotherapy eliminates immunosuppressive hepatic macrophages, increases hepatic T cell survival and reduces hepatic siphoning of T cells. Thus, liver metastases co-opt host peripheral tolerance mechanisms to cause acquired immunotherapy resistance through CD8+ T cell deletion, and the combination of liver-directed radiotherapy and immunotherapy could promote systemic antitumor immunity. Liver metastases reduce clinical and preclinical immune-checkpoint inhibitor efficacy through hepatic siphoning of circulating activated CD8+ T cells, but therapeutic benefit can be improved by combining immunotherapy with liver-directed radiotherapy.

DOI: 10.1038/s41591-020-1131-x

Source: https://www.nature.com/articles/s41591-020-1131-x

Nature Medicine：《自然—医学》，创刊于1995年。隶属于施普林格·自然出版集团，最新IF：87.241
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