Isolation of T cell receptors targeting recurrent neoantigens in hematological malignancies
Isolation of T cell receptors targeting recurrent neoantigens in hematological malignancies
复制标题
针对血液恶性肿瘤中复发性新抗原的 T 细胞受体的分离
DOI：
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发表时间：
2018
期刊：
影响因子：
--
通讯作者：
G. Bendle
中科院分区：
文献类型：
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作者：
Vanessa Tubb;Deborah S. Schrikkema;N. Croft;A. Purcell;C. Linnemann;Manon R. Freriks;Frederick E. Chen;H. Long;Steven P Lee;G. Bendle
突变衍生的新抗原代表了一类重要的肿瘤特异性、肿瘤排斥抗原，并且是癌症 TCR 基因治疗的有吸引力的靶标。大多数此类突变是患者特异性的，针对这些突变需要完全个性化的方法。然而，一些突变在癌症患者中反复出现，代表了更广泛适用的新抗原特异性 TCR 基因治疗的潜在靶点。因此，我们研究了在血液恶性肿瘤中经常发现的一些癌症突变是否编码由常见欧洲高加索人 HLA I 类等位基因呈现的免疫原性新抗原，并且可以形成 TCR 基因治疗的靶点。我们最初专注于鉴定源自钙网蛋白 (CALR) 外显子 9 突变的 HLA I 类新表位，这种突变存在于约 80% 的 JAK2wt 骨髓增生性肿瘤 (MPN) 中。根据 MHC I 类肽预测，预测源自突变 CALR (mCALR) 的许多肽将与 HLA-A*03:01 和 HLA-B*07:02 结合。然而，使用质谱分析和离体 pMHC 多聚体染色，对具有 CALR 外显子 9 突变的 MPN 患者的 PBMC 进行染色，我们发现没有证据表明这些肽被自然加工并呈现在表达 mCALR 的靶细胞表面。接下来，我们开发了一种方案，利用 pMHC 多聚体从健康人类供体 PBMC 中分离 CD8+ T 细胞，这些细胞对 mCALR 和血液恶性肿瘤中经常发现的其他推定新表位具有特异性。使用这种方法，成功分离了对 HLA-A*03:01 和 HLA-B*07:02 呈递的 mCALR 肽以及 HLA-A*11:01 呈递的突变型 FBXW7 (mFBXW7) 肽具有特异性的 CD8+ T 细胞。从 mCALR 特异性 CD8+ T 细胞群中分离出的 TCR 无法识别经过工程改造以表达 mCALR 的靶细胞。相比之下，mFBXW7 特异性 CD8+ T 细胞能够识别经过工程改造表达 mFBXW7 的靶细胞。总之，虽然我们没有发现在研究的 HLA I 类等位基因背景下 mCALR 衍生的新表位呈递的证据，但我们的数据表明 FBXW7 中反复出现的 pR465H 突变可能编码 HLA-A*11:01 呈递的新表位，并且值得进一步研究作为基于 T 细胞的癌症免疫治疗的靶点。
Mutation-derived neoantigens represent an important class of tumour-specific, tumour rejection antigens, and are attractive targets for TCR gene therapy of cancer. The majority of such mutations are patient-specific and targeting these requires a fully personalized approach. However, some mutations are found recurrently among cancer patients, and represent potential targets for neoantigen-specific TCR gene therapy that is more widely applicable. Therefore, we have investigated if some cancer mutations found recurrently in hematological malignancies encode immunogenic neoantigens presented by common European Caucasoid HLA class I alleles and can form targets for TCR gene therapy. We initially focused on identifying HLA class I neoepitopes derived from calreticulin (CALR) exon 9 mutations, found in ~ 80% of JAK2wt myeloproliferative neoplasms (MPN). Based on MHC class I peptide predictions, a number of peptides derived from mutant CALR (mCALR) were predicted to bind to HLA-A*03:01 and HLA-B*07:02. However, using mass spectrometry and ex vivo pMHC multimer staining of PBMC from MPN patients with CALR exon 9 mutations, we found no evidence that these peptides were naturally processed and presented on the surface of mCALR-expressing target cells. We next developed a protocol utilizing pMHC multimers to isolate CD8+ T cells from healthy human donor PBMC that are specific for mCALR and additional putative neoepitopes found recurrently in hematological malignancies. Using this approach, CD8+ T cells specific for HLA-A*03:01- and HLA-B*07:02-presented mCALR peptides and an HLA-A*11:01-presented mutant FBXW7 (mFBXW7) peptide were successfully isolated. TCRs isolated from mCALR-specific CD8+ T cell populations were not able to recognize target cells engineered to express mCALR. In contrast, mFBXW7-specific CD8+ T cells were able to recognize target cells engineered to express mFBXW7. In conclusion, while we found no evidence for mCALR derived neoepitope presentation in the context of the HLA class I alleles studied, our data suggests that the recurrent pR465H mutation in FBXW7 may encode an HLA-A*11:01 presented neoepitope, and warrants further investigation as a target for T cell based immunotherapy of cancer.
影响因子：
158.5
作者：
Hunder, Naomi N.;Wallen, Herschel;Yee, Cassian
通讯作者：
Yee, Cassian
DOI：
10.1056/nejmoa1406498
发表时间：
2014-12-04
期刊：
The New England journal of medicine
影响因子：
--
作者：
Snyder A;Makarov V;Merghoub T;Yuan J;Zaretsky JM;Desrichard A;Walsh LA;Postow MA;Wong P;Ho TS;Hollmann TJ;Bruggeman C;Kannan K;Li Y;Elipenahli C;Liu C;Harbison CT;Wang L;Ribas A;Wolchok JD;Chan TA
通讯作者：
Chan TA
影响因子：
64.8
作者：
Gubin, Matthew M.;Zhang, Xiuli;Schuster, Heiko;Caron, Etienne;Ward, Jeffrey P.;Noguchi, Takuro;Ivanova, Yulia;Hundal, Jasreet;Arthur, Cora D.;Krebber, Willem-Jan;Mulder, Gwenn E.;Toebes, Mireille;Vesely, Matthew D.;Lam, Samuel S. K.;Korman, Alan J.;Allison, James P.;Freeman, Gordon J.;Sharpe, Arlene H.;Pearce, Erika L.;Schumacher, Ton N.;Aebersold, Ruedi;Rammensee, Hans-Georg;Melief, Cornelis J. M.;Mardis, Elaine R.;Gillanders, William E.;Artyomov, Maxim N.;Schreiber, Robert D.
通讯作者：
Schreiber, Robert D.