Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer
Immunologic Recognition of a Shared p53 Mutated Neoantigen in a Patient with Metastatic Colorectal Cancer
复制标题
DOI：
10.1158/2326-6066.cir-18-0686
复制
发表时间：
2019-04-01
影响因子：
10.1
通讯作者：
Rosenberg, Steven A.
中科院分区：
文献类型：
--
作者：
Lo, Winifred;Parkhurst, Maria;Rosenberg, Steven A.
以新抗原为靶点的T细胞过继细胞治疗(ACT)可以在转移性癌症患者中介导持久的反应。针对上皮性癌的共同共同抗原的细胞疗法还没有广泛应用。在这里，我们报告了一名患者识别突变的p53 p.R175H的T细胞受体(TCR)的鉴定和特征，这种突变在部分癌症患者中是共有的。对1例转移性结直肠癌患者的肿瘤浸润性淋巴细胞进行了筛选，以识别突变的新抗原。对突变型p53 p.R175H进行了HL A*0201限制性识别，其最小表位为HMTEVVRHC。用四聚体分选法分离反应性T细胞，鉴定出3个TCR。这些TCR介导了对可商业获得的卵巢癌、子宫癌和骨髓瘤细胞系的识别，以及对NIH患者来源的食管腺癌细胞系的识别，该细胞系内源性表达P53 p.R175H和HLA-A*0201。在用编码HLAA*0201的逆转录病毒转导p53 p.R175H刺状结肠、乳腺和白血病细胞系后，它们也介导了对这些细胞系的识别。这项工作表明，常见的共有突变表位，如在p53中发现的那些，可以引发免疫原性反应，ACT的应用可以扩展到任何癌症组织学既表达HLAA*0201又表达P53 p.R175H突变的患者。
Adoptive cell therapy (ACT) with T cells targeting neoantigens can mediate durable responses in patients with metastatic cancer. Cell therapies targeting common shared antigens for epithelial cancers are not yet broadly available. Here, we report the identification and characterization in one patient of T-cell receptors (TCRs) recognizing mutated p53 p. R175H, which is shared among a subset of patients with cancer. Tumorinfiltrating lymphocytes were screened for recognition of mutated neoantigens in a patient with metastatic colorectal cancer. HLA-A*0201-restricted recognition of mutated p53 p. R175H was identified, and the minimal peptide epitope was HMTEVVRHC. Reactive T cells were isolated by tetramer sort-ing, and three TCRs were identified. These TCRs mediated recognition of commercially available ovarian cancer, uterine carcinoma, and myeloma cell lines, as well as an NIH patientderived esophageal adenocarcinoma line that endogenously expressed p53 p. R175H and HLA-A*0201. They also mediated recognition of p53 p. R175H thorn colon, breast, and leukemia cell lines after transduction with a retrovirus encoding HLAA *0201. This work demonstrates that common shared mutated epitopes such as those found in p53 can elicit immunogenic responses and that the application of ACT may be extended to patients with any cancer histology that expresses both HLAA *0201 and the p53 p. R175H mutation.