Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9.
Enhanced CAR-T activity against established tumors by polarizing human T cells to secrete interleukin-9.
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DOI：
10.1038/s41467-020-19672-2
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发表时间：
2020-11-19
影响因子：
16.6
通讯作者：
Yi Q
中科院分区：
文献类型：
--
作者：
Liu L;Bi E;Ma X;Xiong W;Qian J;Ye L;Su P;Wang Q;Xiao L;Yang M;Lu Y;Yi Q
CAR-T细胞疗法对血液恶性肿瘤有效。然而，相当数量的患者在治疗后复发，部分原因是CAR-T细胞在体内的扩增不良和持久性有限。在这里，我们证明了在Th 9培养条件下极化和扩增的人CAR-T细胞（T9 CAR-T）对已建立的肿瘤具有增强的抗肿瘤活性。与IL 2极化（T1）细胞相比，T9 CAR-T细胞分泌IL 9但很少分泌IFN-γ，表达中枢记忆表型和较低水平的耗竭标志物，并显示出稳健的增殖能力。因此，T9 CAR-T细胞在体内介导比T1 CAR-T细胞更大的抗肿瘤活性，对抗已建立的血液肿瘤和实体瘤。转移后，T9 CAR-T细胞有效地迁移到肿瘤，分化为分泌IFN-γ和颗粒酶-B的效应记忆T细胞，但仍保持为长寿命和过度增殖的T细胞。我们的研究结果对于改善人类癌症基于CAR-T细胞的免疫疗法非常重要。抗原特异性IL 9分泌性CD 4 Th 9和CD 8 Tc 9细胞先前已表征其抗肿瘤特性。在这里，作者表明，与传统的IL-2激活的CAR-T细胞相比，离体极化的Th 9/Tc 9人CAR-T细胞在临床前血液学和实体癌模型中显示出增加的抗肿瘤活性。
CAR-T cell therapy is effective for hematologic malignancies. However, considerable numbers of patients relapse after the treatment, partially due to poor expansion and limited persistence of CAR-T cells in vivo. Here, we demonstrate that human CAR-T cells polarized and expanded under a Th9-culture condition (T9 CAR-T) have an enhanced antitumor activity against established tumors. Compared to IL2-polarized (T1) cells, T9 CAR-T cells secrete IL9 but little IFN-γ, express central memory phenotype and lower levels of exhaustion markers, and display robust proliferative capacity. Consequently, T9 CAR-T cells mediate a greater antitumor activity than T1 CAR-T cells against established hematologic and solid tumors in vivo. After transfer, T9 CAR-T cells migrate effectively to tumors, differentiate to IFN-γ and granzyme-B secreting effector memory T cells but remain as long-lived and hyperproliferative T cells. Our findings are important for the improvement of CAR-T cell-based immunotherapy for human cancers. Antigen-specific IL9-secreting CD4 Th9 and CD8 Tc9 cells have been previously characterized for their anti-tumour properties. Here, the authors show that ex vivo polarized Th9/Tc9 human CAR-T cells display increased anti-tumor activity in pre-clinical haematological and solid cancer models compared to conventional IL-2 activated CAR-T cells.
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影响因子：
64.5
作者：
GYURIS, J;GOLEMIS, E;BRENT, R
通讯作者：
BRENT, R
影响因子：
82.9
作者：
Long, Adrienne H.;Haso, Waleed M.;Shern, Jack F.;Wanhainen, Kelsey M.;Murgai, Meera;Ingaramo, Maria;Smith, Jillian P.;Walker, Alec J.;Kohler, M. Eric;Venkateshwara, Vikas R.;Kaplan, Rosandra N.;Patterson, George H.;Fry, Terry J.;Orentas, Rimas J.;Mackall, Crystal L.
通讯作者：
Mackall, Crystal L.
影响因子：
20.3
作者：
Kochenderfer, James N.;Wilson, Wyndham H.;Rosenberg, Steven A.
通讯作者：
Rosenberg, Steven A.
影响因子：
20.3
作者：
Gardner, Rebecca;Wu, David;Turtle, Cameron J.
通讯作者：
Turtle, Cameron J.
DOI：
10.1056/nejmoa1407222
发表时间：
2014-10-16
期刊：
The New England journal of medicine
影响因子：
--
作者：
Maude SL;Frey N;Shaw PA;Aplenc R;Barrett DM;Bunin NJ;Chew A;Gonzalez VE;Zheng Z;Lacey SF;Mahnke YD;Melenhorst JJ;Rheingold SR;Shen A;Teachey DT;Levine BL;June CH;Porter DL;Grupp SA
通讯作者：
Grupp SA