Identification of novel HLA-restricted preferentially expressed antigen in melanoma peptides to facilitate off-the-shelf tumor-associated antigen-specific T-cell therapies.
Identification of novel HLA-restricted preferentially expressed antigen in melanoma peptides to facilitate off-the-shelf tumor-associated antigen-specific T-cell therapies.
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DOI：
10.1016/j.jcyt.2021.03.001
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发表时间：
2021-08
期刊：
影响因子：
4.5
通讯作者：
Bollard CM
中科院分区：
文献类型：
--
作者：
Stanojevic M;Hont AB;Geiger A;O'Brien S;Ulrey R;Grant M;Datar A;Lee PH;Lang H;Cruz CRY;Hanley PJ;Barrett AJ;Keller MD;Bollard CM
黑色素瘤中的前列腺表达抗原（PRAME）是在许多人类恶性肿瘤中过度表达而在健康组织中表达不足或缺失的癌症-睾丸抗原，使其成为抗癌免疫治疗的良好靶点。为患有复发性或难治性实体瘤和表达PRAME抗原的血液恶性肿瘤的患者开发有效的现成过继性T细胞疗法需要鉴定由TAA-T细胞产物识别的MHC I类和II类PRAME抗原。因此，我们着手扩展HLA限制性PRAME肽表位的库，使其超出少数已经表征的表位。使用跨越整个PRAME蛋白质序列的125个重叠15-mer肽的肽文库来鉴定HLA I类和II类限制性表位。我们还确定了所鉴定的表位的HLA限制性。从12个健康供体的PBMC成功产生PRAME特异性T细胞产物。离体扩增的T细胞是多克隆的，由在体外引起抗肿瘤活性的CD4+和CD8 + T细胞组成。鉴定了9个MHC I类限制性PRAME表位（7个新的和2个先前描述的）。我们还鉴定了16个15-mer肽序列，证实为CD4限制性表位。来源于健康供体的TAA T细胞识别广泛的CD4+和CD8 + HLA限制性PRAME表位，其可用于选择合适的供体以产生现成的TAA特异性T细胞。
Preferentially expressed antigen in melanoma (PRAME) is a cancer-testis antigen overexpressed in many human malignancies while poorly expressed or absent in healthy tissues, making it a good target for anticancer immunotherapy. Development of an effective off-the-shelf adoptive T-cell therapy for patients with relapsed or refractory solid tumors and hematological malignancies expressing PRAME antigen requires the identification of MHC class I and II PRAME antigens recognized by the TAA-T cell product. We therefore set out to extend the repertoire of HLA-restricted PRAME peptide epitopes beyond the few already characterized. Peptide libraries of 125 overlapping 15-mer peptides spanning the entire PRAME protein sequence were used to identify HLA class I and class II-restricted epitopes. We also determined the HLA-restriction of the identified epitopes. PRAME-specific T-cell products were successfully generated from PBMCs of 12 healthy donors. Ex-vivo expanded T-cells were polyclonal, consisting of both CD4+ and CD8+ T-cells which elicited anti-tumor activity in vitro. Nine MHC class I-restricted PRAME epitopes were identified (seven novel and two previously described). We also characterized sixteen 15-mer peptide sequences confirmed as CD4-restricted epitopes. TAA T-cells derived from healthy donors recognize a broad range of CD4+ and CD8+ HLA-restricted PRAME epitopes, which could be used to select suitable donors for generating off-the-shelf TAA-specific T-cells.
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影响因子：
4.8
作者：
O'Reilly RJ;Prockop S;Hasan AN;Koehne G;Doubrovina E
通讯作者：
Doubrovina E
影响因子：
20.3
作者：
Leen, Ann M.;Bollard, Catherine M.;Heslop, Helen E.
通讯作者：
Heslop, Helen E.
影响因子：
17.1
作者：
Chapuis AG;Ragnarsson GB;Nguyen HN;Chaney CN;Pufnock JS;Schmitt TM;Duerkopp N;Roberts IM;Pogosov GL;Ho WY;Ochsenreither S;Wölfl M;Bar M;Radich JP;Yee C;Greenberg PD
通讯作者：
Greenberg PD
DOI：
10.1084/jem.193.1.73
发表时间：
2001-01-01
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Kessler JH;Beekman NJ;Bres-Vloemans SA;Verdijk P;van Veelen PA;Kloosterman-Joosten AM;Vissers DC;ten Bosch GJ;Kester MG;Sijts A;Wouter Drijfhout J;Ossendorp F;Offringa R;Melief CJ
通讯作者：
Melief CJ
影响因子：
20.3
作者：
Hanley, Patrick J.;Cruz, Conrad Russell Young;Bollard, Catherine M.
通讯作者：
Bollard, Catherine M.