Platelet-derived microparticles adoptively transfer integrin β3 to promote antitumor effect of tumor-infiltrating T cells.
Platelet-derived microparticles adoptively transfer integrin β3 to promote antitumor effect of tumor-infiltrating T cells.
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DOI：
10.1080/2162402x.2024.2304963
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发表时间：
2024
期刊：
影响因子：
7.2
通讯作者：
中科院分区：
文献类型：
--
作者：
大约三分之二的肝细胞癌（HCC）被认为是一种“冷肿瘤”，其特征是肿瘤浸润性T细胞很少，免疫抑制细胞丰富。Cilengitide是一种整合素αvβ3抑制剂，作为一种潜在的抗癌药物在临床试验中失败。这种失败意味着整合素αvβ3可能在免疫细胞中起重要作用。然而，整合素αvβ3在肝癌患者T细胞中的表达及其潜在作用尚不清楚。在此，我们建立了两种肝癌模型，发现西仑吉肽对肝癌微环境具有双重作用，通过对T细胞发挥抗肿瘤作用和免疫抑制作用。这可能部分解释了西仑吉肽在临床试验中的失败。在临床标本中，HCC浸润性T细胞表现出整合素β3表达和活化缺陷，这与T细胞向肿瘤中的浸润不良相关。此外，整合素β3在体外作为一种正性免疫调节分子，促进T细胞浸润和辅助性T细胞1型免疫应答。T细胞与血小板衍生微粒（platelet-derived microparticles，PMPs）共培养实验表明，PMPs可过继转移整合素β3至T细胞，并正向调节T细胞免疫应答。这一过程由网格蛋白依赖的内吞作用和巨胞饮作用介导。我们的数据表明，肝癌浸润性T细胞上的整合素β3缺陷可能参与了免疫抑制肿瘤微环境的形成。PMPs将整合素β3转运至T细胞，积极调节T细胞免疫应答，为肝癌的免疫治疗提供了新的思路。
Approximately two-thirds of hepatocellular carcinoma (HCC) is considered a “cold tumor” characterized by few tumor-infiltrating T cells and an abundance of immunosuppressive cells. Cilengitide, an integrin αvβ3 inhibitor, has failed in clinical trials as a potential anticancer drug. This failure implies that integrin αvβ3 may play an important role in immune cells. However, the expression and potential role of integrin αvβ3 in T cells of HCC patients remain unknown. Here, we established two HCC models and found that cilengitide had a dual effect on the HCC microenvironment by exerting both antitumor effect and immunosuppressive effect on T cells. This may partly explain the failure of cilengitide in clinical trials. In clinical specimens, HCC-infiltrating T cells exhibited deficient expression and activation of integrin β3, which was associated with poor T-cell infiltration into tumors. Additionally, integrin β3 functioned as a positive immunomodulatory molecule to facilitate T-cell infiltration and T helper 1-type immune response in vitro. Furthermore, T cells and platelet-derived microparticles (PMPs) co-culture assay revealed that PMPs adoptively transferred integrin β3 to T cells and positively regulated T cell immune response. This process was mediated by clathrin-dependent endocytosis and macropinocytosis. Our data demonstrate that integrin β3 deficiency on HCC-infiltrating T cells may be involved in shaping the immunosuppressive tumor microenvironment. PMPs transfer integrin β3 to T cells and positively regulate T cell immune response, which may provide a new insight into immune therapy of HCC.
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影响因子：
24.5
作者：
Montironi, Carla;Castet, Florian;Haber, Philipp K.;Pinyol, Roser;Torres-Martin, Miguel;Fontanals, Laura Torrens;Mesropian, Agavni;Wang, Huan;Puigvehi, Marc;Maeda, Miho;Leow, Wei Qiang;Harrod, Elizabeth;Taik, Patricia;Chinburen, Jigjidsuren;Taivanbaatar, Erdenebileg;Chinbold, Enkhbold;Arques, Manel Sole;Donovan, Michael;Thung, Swan;Neely, Jaclyn;Mazzaferro, Vincenzo;Anderson, Jeffrey;Roayaie, Sasan;Schwartz, Myron;Villanueva, Augusto;Friedman, Scott L.;Uzilov, Andrew;Sia, Daniela;Llovet, Josep M.
通讯作者：
Llovet, Josep M.
影响因子：
16.6
作者：
Larochelle C;Uphaus T;Broux B;Gowing E;Paterka M;Michel L;Dudvarski Stankovic N;Bicker F;Lemaître F;Prat A;Schmidt MHH;Zipp F
通讯作者：
Zipp F
影响因子：
5.4
作者：
通讯作者：
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影响因子：
50.3
作者：
Ma, Chi;Fu, Qiong;Diggs, Laurence P.;Mcvey, John C.;McCallen, Justin;Wabitsch, Simon;Ruf, Benjamin;Brown, Zachary;Heinrich, Bernd;Zhang, Qianfei;Rosato, Umberto;Wang, Sophie;Cui, Linda;Berzofsky, Jay A.;Kleiner, David E.;Bosco, Dale B.;Wu, Long-Jun;Lai, Chunwei Walter;Rotman, Yaron;Xie, Changqing;Korangy, Firouzeh;Greten, Tim F.
通讯作者：
Greten, Tim F.
影响因子：
9
作者：
Liu, Jian;Guo, Yongjian;Zhang, Ruitian;Xu, Ye;Luo, Chengju;Wang, Rui;Xu, Shu;Wei, Libin
通讯作者：
Wei, Libin