小柯机器人

德国癌症研究中心Amir Abdollahi和默克EMD Serono研发中心Yan Lan团队的最新研究表明，靶向转化生长因子β(TGF-β)/程序性细胞死亡配体1 (PD-L1)联合化疗通过重编程肿瘤微环境来克服免疫逃避。2021年9月9日，《癌细胞》在线发表了这项成果。

研究人员发现了一种具有同时抑制TGF-β和PD-L1双重功能的融合蛋白bintrafusp alfa (BA)，可有效地与放疗协同作用，从而在免疫浸润较差的多种抗药性小鼠肿瘤模型中获得更高的小鼠存活率。BA+局部放疗(RT) (BART) 组合增加肿瘤浸润性白细胞，重新编程肿瘤微环境，并减弱RT诱导的纤维化，导致肿瘤免疫重塑和减弱自发性肺转移。同时，BART的有益作用会因细胞毒性CD8⁺ T细胞的减少而部分逆转。

有趣的是，BA将靶向TGF-β可将PD-L1⁺限制在内皮和M2/脂肪成纤维细胞样细胞区室，从而减弱了晚期RT诱导的肺纤维化。总之，该结果表明BART组合有可能根除耐药肿瘤，同时保护正常组织功能，进一步支持其临床转化潜能。

据悉，RT可引发免疫原性抗肿瘤反应，但免疫逃避和组织重塑会抵消部分抗肿瘤活性，例如，通过上调PD-L1和TGF-β诱发的抵抗反应。

附：英文原文

Title: Simultaneous targeting of TGF-β/PD-L1 synergizes with radiotherapy by reprogramming the tumor microenvironment to overcome immune evasion

Author: Yan Lan, Mahmoud Moustafa, Maximillian Knoll, Chunxiao Xu, Jennifer Furkel, Adam Lazorchak, Tsz-Lun Yeung, Sayed-Mohammad Hasheminasab, Molly H. Jenkins, Sarah Meister, Huakui Yu, Julian Schlegel, Bo Marelli, Zili Tang, Guozhong Qin, Carmen Klein, Jin Qi, Cheng Zhou, George Locke, Damir Krunic, Melissa G. Derner, Christian Schwager, Rachel E. Fontana, Katharina Kriegsmann, Feng Jiang, Katrin Rein, Mark Kriegsmann, Juergen Debus, Kin-Ming Lo, Amir Abdollahi

Issue&Volume: 2021-09-09

Abstract: Localized radiotherapy (RT) induces an immunogenic antitumor response that is in part counterbalanced by activation of immune evasive and tissue remodeling processes, e.g., via upregulation of programmed cell death-ligand 1 (PD-L1) and transforming growth factor β (TGF-β). We report that a bifunctional fusion protein that simultaneously inhibits TGF-β and PD-L1, bintrafusp alfa (BA), effectively synergizes with radiotherapy, leading to superior survival in multiple therapy-resistant murine tumor models with poor immune infiltration. The BA + RT (BART) combination increases tumor-infiltrating leukocytes, reprograms the tumor microenvironment, and attenuates RT-induced fibrosis, leading to reconstitution of tumor immunity and regression of spontaneous lung metastases. Consistently, the beneficial effects of BART are in part reversed by depletion of cytotoxic CD8+ T cells. Intriguingly, targeting of the TGF-β trap to PD-L1+ endothelium and the M2/lipofibroblast-like cell compartment by BA attenuated late-stage RT-induced lung fibrosis. Together, the results suggest that the BART combination has the potential to eradicate therapy-resistant tumors while sparing normal tissue, further supporting its clinical translation.

DOI: 10.1016/j.ccell.2021.08.008

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(21)00448-7

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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