当前位置:科学网首页 > 小柯机器人 >详情
整合素αvβ6–TGFβ–SOX4途径驱动三阴性乳腺癌的免疫逃逸
作者:小柯机器人 发布时间:2021/1/3 16:01:15

美国丹娜-法伯癌症研究所Kai W. Wucherpfennig研究小组发现,整合素αvβ6–TGFβ–SOX4途径驱动三阴性乳腺癌的免疫逃逸。该研究于2020年12月31日在线发表于国际一流学术期刊《癌细胞》。

研究人员发现,转录因子SOX4是T细胞介导的三阴性乳腺癌(TNBC)细胞毒性的重要抗性机制。机理研究表明,肿瘤细胞中SOX4的失活会增加许多固有免疫和适应性免疫途径中的基因表达,这对于保护肿瘤免疫至关重要。SOX4的表达受肿瘤细胞表面上的整合素αvβ6受体调节,该受体激活潜在前体中的TGFβ。

整合素αvβ6/8阻断单克隆抗体(mAb)能够抑制SOX4表达并使TNBC细胞对细胞毒性T细胞敏感。在对PD-1阻断反应不良的高度转移性鼠TNBC模型中,这种整合素mAb诱导了实质性的生存获益。因此,针对整联蛋白αvβ6-TGFβ–SOX4途径的靶向为TNBC和其他上皮性高度侵袭性人类癌症提供了治疗机会。

据介绍,癌症免疫疗法对源自上皮组织的许多实体瘤(包括TNBC)显示出有限的疗效。

附:英文原文

Title: Integrin αvβ6–TGFβ–SOX4 Pathway Drives Immune Evasion in Triple-Negative Breast Cancer

Author: Archis Bagati, Sushil Kumar, Peng Jiang, Jason Pyrdol, Angela E. Zou, Anze Godicelj, Nathan D. Mathewson, Adam N.R. Cartwright, Paloma Cejas, Myles Brown, Anita Giobbie-Hurder, Deborah Dillon, Judith Agudo, Elizabeth A. Mittendorf, X. Shirley Liu, Kai W. Wucherpfennig

Issue&Volume: 2020-12-31

Abstract: Cancer immunotherapy shows limited efficacy against many solid tumors that originatefrom epithelial tissues, including triple-negative breast cancer (TNBC). We identifythe SOX4 transcription factor as an important resistance mechanism to T cell-mediatedcytotoxicity for TNBC cells. Mechanistic studies demonstrate that inactivation ofSOX4 in tumor cells increases the expression of genes in a number of innate and adaptiveimmune pathways important for protective tumor immunity. Expression of SOX4 is regulatedby the integrin αvβ6 receptor on the surface of tumor cells, which activates TGFβfrom a latent precursor. An integrin αvβ6/8-blocking monoclonal antibody (mAb) inhibitsSOX4 expression and sensitizes TNBC cells to cytotoxic T cells. This integrin mAbinduces a substantial survival benefit in highly metastatic murine TNBC models poorlyresponsive to PD-1 blockade. Targeting of the integrin αvβ6-TGFβ–SOX4 pathway thereforeprovides therapeutic opportunities for TNBC and other highly aggressive human cancersof epithelial origin.

DOI: 10.1016/j.ccell.2020.12.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(20)30608-5

期刊信息

Cancer Cell:《癌细胞》,创刊于2002年。隶属于细胞出版社,最新IF:23.916
官方网址:https://www.cell.com/cancer-cell/home
投稿链接:https://www.editorialmanager.com/cancer-cell/default.aspx