Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes
Isolation of neoantigen-specific T cells from tumor and peripheral lymphocytes
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DOI：
10.1172/jci82416
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发表时间：
2015-10-01
影响因子：
15.9
通讯作者：
Robbins, Paul F.
中科院分区：
文献类型：
--
作者：
Cohen, Cyrille J.;Gartner, Jared J.;Robbins, Paul F.
介导转移性黑色素瘤完全消退的连续转移的肿瘤浸润性T淋巴细胞（TIL）已显示识别自体肿瘤表达的突变表位。在这里，为了尝试开发一种策略，以促进突变的抗原特异性T细胞的分离、扩增和研究，我们对从8例转移性黑色素瘤患者中分离的匹配肿瘤和正常DNA进行了全外显子组测序。使用肽-MHC结合算法鉴定候选突变表位，合成这些表位并用于产生MHC四聚体组，评估其与用于治疗患者的肿瘤抑制物和培养的TIL的结合。该策略导致从8名受试患者中的5名鉴定出9个突变表位。与9个表位中的8个表位反应的细胞可以从自体外周血中分离，其中它们以估计在0.4%和0.002%之间的范围内的频率被检测到。据我们所知，这首次证明了在免疫治疗之前从患者外周血中成功分离突变反应性T细胞，这可能为设计个性化免疫疗法来治疗晚期癌症患者提供基础。
Adoptively transferred tumor-infiltrating T lymphocytes (TILs) that mediate complete regression of metastatic melanoma have been shown to recognize mutated epitopes expressed by autologous tumors. Here, in an attempt to develop a strategy for facilitating the isolation, expansion, and study of mutated antigen-specific T cells, we performed whole-exome sequencing on matched tumor and normal DNA isolated from 8 patients with metastatic melanoma. Candidate mutated epitopes were identified using a peptide-MHC-binding algorithm, and these epitopes were synthesized and used to generate panels of MHC tetramers that were evaluated for binding to tumor digests and cultured TILs used for the treatment of patients. This strategy resulted in the identification of 9 mutated epitopes from 5 of the 8 patients tested. Cells reactive with 8 of the 9 epitopes could be isolated from autologous peripheral blood, where they were detected at frequencies that were estimated to range between 0.4% and 0.002%. To the best of our knowledge, this represents the first demonstration of the successful isolation of mutation-reactive T cells from patients' peripheral blood prior to immune therapy, potentially providing the basis for designing personalized immunotherapies to treat patients with advanced cancer.