肝轉移可通過巨噬細胞介導的T細胞消除來抑制免疫療法
作者：
小柯機器人發布時間：2021/1/6 17:19:37
美國密西根大學Weiping Zou、Michael D. Green等研究人員合作發現，肝轉移通過巨噬細胞介導的T細胞消除來抑制免疫療法。相關論文於2021年1月4日在線發表在《自然—醫學》雜誌上。
研究人員發現，肝轉移系統地降低了患者和臨床前模型的免疫治療效果。肝轉移患者從免疫治療中獲得的獲益有限，而與其他已建立的反應生物標誌物無關。在多個小鼠模型中，研究人員顯示肝轉移灶從系統循環中吸出激活的CD8+T細胞。在肝臟中，活化的抗原特異性Fas+CD8+T細胞在與FasL+CD11b+F4/80+單核細胞衍生的巨噬細胞相互作用後經歷凋亡。因此，在臨床前模型中，肝轉移會形成全身性免疫荒漠。同樣，患有肝轉移的患者外周血T細胞數量減少，腫瘤T細胞多樣性和功能降低。
在臨床前模型中，肝定向放射治療消除了免疫抑制性肝巨噬細胞，增加了肝T細胞存活率並減少了肝對T細胞的虹吸。因此，肝轉移選擇宿主外周耐受機制，通過CD8+T細胞缺失引起獲得性免疫治療抗性，並且肝定向放療和免疫治療的結合可以促進全身性抗腫瘤免疫。
據悉，轉移是癌症死亡的主要原因，並且癌症經常轉移到肝臟。尚不清楚肝臟免疫耐受機制是否有助於癌癥結果。
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