Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors.
Combined tumor-directed recruitment and protection from immune suppression enable CAR T cell efficacy in solid tumors.
复制标题
DOI：
10.1126/sciadv.abi5781
复制
发表时间：
2021-06
期刊：
影响因子：
13.6
通讯作者：
Kobold S
中科院分区：
文献类型：
--
作者：
Cadilha BL;Benmebarek MR;Dorman K;Oner A;Lorenzini T;Obeck H;Vänttinen M;Di Pilato M;Pruessmann JN;Stoiber S;Huynh D;Märkl F;Seifert M;Manske K;Suarez-Gosalvez J;Zeng Y;Lesch S;Karches CH;Heise C;Gottschlich A;Thomas M;Marr C;Zhang J;Pandey D;Feuchtinger T;Subklewe M;Mempel TR;Endres S;Kobold S
定向迁移和免疫抑制屏蔽的结合使T细胞治疗实体瘤有效。CAR - T细胞疗法在实体瘤中仍然无效，主要是由于肿瘤部位浸润不良和T细胞抑制。T调节性细胞（Treg）通过转化生长因子-β (TGF-β)等抑制因子抑制免疫应答。表达C-C趋化因子受体8 （CCR8）的Treg细胞与实体瘤的不良预后相关。我们假设CCR8可以被利用来将效应T细胞重定向到肿瘤部位，而显性阴性的TGF-β受体2 （DNR）可以同时保护它们不受TGF-β的影响。我们发现来自活化T细胞的CCL1增强了CCR8+ T细胞募集到肿瘤部位的反馈回路。这种持续和改善的工程T细胞浸润与TGF-β屏蔽协同作用，以提高治疗效果。我们的研究结果表明，将CCR8和DNR添加到CAR - T细胞中可以使它们在实体肿瘤中有效。
The combination of directed migration and immunosuppressive shielding enables effective T cell therapy in solid tumors. CAR T cell therapy remains ineffective in solid tumors, due largely to poor infiltration and T cell suppression at the tumor site. T regulatory (Treg) cells suppress the immune response via inhibitory factors such as transforming growth factor–β (TGF-β). Treg cells expressing the C-C chemokine receptor 8 (CCR8) have been associated with poor prognosis in solid tumors. We postulated that CCR8 could be exploited to redirect effector T cells to the tumor site while a dominant-negative TGF-β receptor 2 (DNR) can simultaneously shield them from TGF-β. We identified that CCL1 from activated T cells potentiates a feedback loop for CCR8+ T cell recruitment to the tumor site. This sustained and improved infiltration of engineered T cells synergized with TGF-β shielding for improved therapeutic efficacy. Our results demonstrate that addition of CCR8 and DNR into CAR T cells can render them effective in solid tumors.
登录
查看更多内容
影响因子：
64.8
作者：
Eyquem J;Mansilla-Soto J;Giavridis T;van der Stegen SJ;Hamieh M;Cunanan KM;Odak A;Gönen M;Sadelain M
通讯作者：
Sadelain M
影响因子：
17.1
作者：
Brentjens RJ;Davila ML;Riviere I;Park J;Wang X;Cowell LG;Bartido S;Stefanski J;Taylor C;Olszewska M;Borquez-Ojeda O;Qu J;Wasielewska T;He Q;Bernal Y;Rijo IV;Hedvat C;Kobos R;Curran K;Steinherz P;Jurcic J;Rosenblat T;Maslak P;Frattini M;Sadelain M
通讯作者：
Sadelain M
影响因子：
30.5
作者：
D'Amico, G;Frascaroli, G;Mantovani, A
通讯作者：
Mantovani, A
影响因子：
32.4
作者：
Gorelik, L;Flavell, RA
通讯作者：
Flavell, RA
带有嵌合抗原受体的T细胞具有有效的抗肿瘤作用，可以在晚期白血病患者中建立记忆。
影响因子：
17.1
作者：
Kalos M;Levine BL;Porter DL;Katz S;Grupp SA;Bagg A;June CH
通讯作者：
June CH