Endogenous CD4+ thorn T Cells Recognize Neoantigens in Lung Cancer Patients, Including Recurrent Oncogenic KRAS and ERBB2 (Her2) Driver Mutations
Endogenous CD4+ thorn T Cells Recognize Neoantigens in Lung Cancer Patients, Including Recurrent Oncogenic KRAS and ERBB2 (Her2) Driver Mutations
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DOI：
10.1158/2326-6066.cir-18-0402
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发表时间：
2019-06-01
影响因子：
10.1
通讯作者：
Riddell, Stanley R.
中科院分区：
文献类型：
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作者：
Veatch, Joshua R.;Jesernig, Brenda L.;Riddell, Stanley R.
对癌症中突变基因编码的新抗原具有特异性的T细胞越来越多地被认为是免疫检查点抑制剂治疗或过继细胞转移后肿瘤破坏的介质。大部分的焦点都集中在鉴定由I类MHC呈递给CD 8（+）刺T细胞的表位上。然而，CD 4（+）刺II类MHC限制性T细胞已被证明在抗肿瘤免疫中具有重要作用。不幸的是，癌症患者中CD 8（+）刺或CD 4（+）刺T细胞识别的绝大多数新抗原来自随机突变，并且是患者特异性的。在这里，我们筛选了5名非小细胞肺癌（NSCLC）患者的血液中对候选突变编码新表位的T细胞应答。检测到对8.8%的筛选抗原的T细胞应答，每个患者鉴定出1至7种抗原。大多数反应是随机的，患者特异性突变。然而，在两名患者中鉴定出识别复发性KRAS（G12 V）和ERBB 2（Her 2）内部串联重复（ITD）致癌驱动突变，但不识别相应野生型序列的CD 4（+）刺T细胞。分离了两种不同的对KRAS（G12 V）特异性的T细胞受体（TCR）和一种对Her 2-ITD特异性的T细胞受体，并在转染到T细胞中时赋予抗原特异性。深度测序鉴定了肿瘤中的Her 2-ITD特异性TCR，但未鉴定出非相邻肺。我们的研究结果表明，CD 4（+）刺T细胞对新抗原的反应，包括复发性驱动突变，可以来自NSCLC患者的血液。这些数据支持使用过继转移或疫苗接种来增加CD 4（+）刺新抗原特异性T细胞，并阐明其在人类抗肿瘤免疫中的作用。
T cells specific for neoantigens encoded by mutated genes in cancers are increasingly recognized as mediators of tumor destruction after immune-checkpoint inhibitor therapy or adoptive cell transfer. Much of the focus has been on identifying epitopes presented to CD8(+) thorn T cells by class I MHC. However, CD4(+) thorn class II MHC-restricted T cells have been shown to have an important role in antitumor immunity. Unfortunately, the vast majority of neoantigens recognized by CD8(+) thorn or CD4(+) thorn T cells in cancer patients result from random mutations and are patient-specific. Here, we screened the blood of 5 non-small cell lung cancer (NSCLC) patients for T-cell responses to candidate mutation-encoded neoepitopes. T-cell responses were detected to 8.8% of screened antigens, with 1 to 7 antigens identified per patient. A majority of responses were to random, patient-specific mutations. However, CD4(+) thorn T cells that recognized the recurrent KRAS(G12V) and the ERBB2 (Her2) internal tandem duplication (ITD) oncogenic driver mutations, but not the corresponding wild-type sequences, were identified in two patients. Two different T-cell receptors (TCR) specific for KRAS(G12V) and one T-cell receptor specific for Her2-ITD were isolated and conferred antigen specificity when transfected into T cells. Deep sequencing identified the Her2-ITD-specific TCR in the tumor but not nonadjacent lung. Our results showed that CD4(+) thorn T-cell responses to neoantigens, including recurrent driver mutations, can be derived from the blood of NSCLC patients. These data support the use of adoptive transfer or vaccination to augment CD4(+) thorn neoantigen-specific T cells and elucidate their role in human antitumor immunity.