Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8(+) T cells.
Checkpoint blockade immunotherapy reshapes the high-dimensional phenotypic heterogeneity of murine intratumoural neoantigen-specific CD8(+) T cells.
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DOI：
10.1038/s41467-017-00627-z
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发表时间：
2017-09-15
影响因子：
16.6
通讯作者：
Newell EW
中科院分区：
文献类型：
--
作者：
Fehlings M;Simoni Y;Penny HL;Becht E;Loh CY;Gubin MM;Ward JP;Wong SC;Schreiber RD;Newell EW
由于肿瘤抗原特异性T细胞的数量很少，对携带肿瘤的个体中新抗原特异性CD8+T细胞的分析是具有挑战性的。在这里，我们展示了多重组合四聚体染色的质量细胞术可以识别和表征新抗原特异的CD8+T细胞，这些T细胞在小鼠体内携带着对检查点阻断免疫治疗敏感的T3甲基胆蒽诱导的肉瘤。在81个候选抗原中，我们在荷瘤小鼠的肿瘤、脾和淋巴结中发现了同时与两种已知新抗原结合的T细胞。高维表型分析显示，抗原特异性的肿瘤浸润性T细胞具有高度异质性。我们进一步表明，在接受抗CTLA-4或抗PD-1免疫治疗的小鼠中，新抗原特异性T细胞表现出不同的表型特征，而它们的外周对应细胞不受这些治疗的影响。我们的结果为深入了解新抗原特异性T细胞的性质和检查点阻断免疫疗法的效果提供了依据。免疫检查点阻断(ICB)疗法可以释放抗肿瘤T细胞反应。在这里，作者通过结合MHC四聚体、质量细胞术和高维分析表明，新抗原特异性的肿瘤浸润性T细胞是高度异质性的，并受到ICB的调节。
The analysis of neoantigen-specific CD8+ T cells in tumour-bearing individuals is challenging due to the small pool of tumour antigen-specific T cells. Here we show that mass cytometry with multiplex combinatorial tetramer staining can identify and characterize neoantigen-specific CD8+ T cells in mice bearing T3 methylcholanthrene-induced sarcomas that are susceptible to checkpoint blockade immunotherapy. Among 81 candidate antigens tested, we identify T cells restricted to two known neoantigens simultaneously in tumours, spleens and lymph nodes in tumour-bearing mice. High-dimensional phenotypic profiling reveals that antigen-specific, tumour-infiltrating T cells are highly heterogeneous. We further show that neoantigen-specific T cells display a different phenotypic profile in mice treated with anti-CTLA-4 or anti-PD-1 immunotherapy, whereas their peripheral counterparts are not affected by the treatments. Our results provide insights into the nature of neoantigen-specific T cells and the effects of checkpoint blockade immunotherapy. Immune checkpoint blockade (ICB) therapies can unleash anti-tumour T-cell responses. Here the authors show, by integrating MHC tetramer multiplexing, mass cytometry and high-dimensional analyses, that neoantigen-specific, tumour-infiltrating T cells are highly heterogeneous and are subjected to ICB modulations.
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影响因子：
64.5
作者：
Kaech, SM;Hemby, S;Ahmed, R
通讯作者：
Ahmed, R
影响因子：
64.8
作者：
Matsushita, Hirokazu;Vesely, Matthew D.;Koboldt, Daniel C.;Rickert, Charles G.;Uppaluri, Ravindra;Magrini, Vincent J.;Arthur, Cora D.;White, J. Michael;Chen, Yee-Shiuan;Shea, Lauren K.;Hundal, Jasreet;Wendl, Michael C.;Demeter, Ryan;Wylie, Todd;Allison, James P.;Smyth, Mark J.;Old, Lloyd J.;Mardis, Elaine R.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.
影响因子：
11.2
作者：
Cohen, AD;Diab, A;Houghton, AN
通讯作者：
Houghton, AN
DOI：
10.1126/science.1198704
发表时间：
2011-05-06
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Bendall SC;Simonds EF;Qiu P;Amir el-AD;Krutzik PO;Finck R;Bruggner RV;Melamed R;Trejo A;Ornatsky OI;Balderas RS;Plevritis SK;Sachs K;Pe'er D;Tanner SD;Nolan GP
通讯作者：
Nolan GP
影响因子：
3.7
作者：
Groom JR;Luster AD
通讯作者：
Luster AD