Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, University of Chile, 8380453 Santiago, Chile; Science for Life Laboratory, Centre for Infectious Medicine (CIM), Department of Medicine, Karolinska University Hospital Huddinge, Karolinska Institute, Stockholm, Sweden; Department of Conservative Dentistry, Faculty of Dentistry, University of Chile, 8380492 Santiago, Chile.
Millennium Institute on Immunology and Immunotherapy, Faculty of Medicine, University of Chile, 8380453 Santiago, Chile.
Immunobiology. 2014 Mar;219(3):189-97. doi: 10.1016/j.imbio.2013.10.002. Epub 2013 Oct 12.
Melanocortin 1 Receptor (MC1R) is expressed in a majority of melanoma biopsies and cell lines. We previously demonstrated that three hydrophobic low-affinity HLA-A2-restricted MC1R-derived peptides: MC1R291-298, MC1R244-252 and MC1R283-291 can elicit cytotoxic T-lymphocytes (CTL) responses from normal donor peripheral blood lymphocytes (PBL). Moreover, peptide-specific CTL recognized a panel of MHC-matched melanomas, demonstrating that human melanoma cell lines naturally present MC1R epitopes. However, the natural presence of MC1R-specific T cells in melanoma patient's tumour and blood remains unknown.
The presence of anti-MC1R specific CD8(+) T cells was established in a population of melanoma-specific T cells derived from peripheral blood mononuclear cells (PBMC) and tumour-infiltrating lymphocytes (TIL) from HLA-A2(+) melanoma patients.
CTLs specific for the three MC1R-derived peptides that lysed allogeneic HLA-A2(+)MC1R(+) melanomas were elicited from PBMC, demonstrating the existence of an anti-MC1R T cell repertoire in melanoma patients. Moreover, TILs also recognized MC1R epitopes and HLA-A2(+) melanoma cell lines. Finally, HLA-A2/MC1R244-specific CD8(+) T cell clones derived from TILs and a subset of MC1R291 specific TILs were identified using HLA-A2/MC1R tetramers.
Our results demonstrate that MC1R-derived peptides are common immunogenic epitopes for melanoma-specific CTLs and TILs, and may thus be useful for the development of anti-melanoma immunotherapy.
黑色素皮质素 1 受体（MC1R）在大多数黑色素瘤活检和细胞系中表达。我们之前证明，三种疏水性低亲和力 HLA-A2 限制性 MC1R 衍生肽：MC1R291-298、MC1R244-252 和 MC1R283-291 可以从正常供体外周血淋巴细胞（PBL）中引发细胞毒性 T 淋巴细胞（CTL）反应。此外，肽特异性 CTL 识别了一组 MHC 匹配的黑色素瘤，证明人类黑色素瘤细胞系天然存在 MC1R 表位。然而，MC1R 特异性 T 细胞在黑色素瘤患者肿瘤和血液中的自然存在仍不清楚。
从 HLA-A2+黑色素瘤患者的外周血单核细胞（PBMC）和肿瘤浸润淋巴细胞（TIL）中分离出黑色素瘤特异性 T 细胞，确定其是否存在抗-MC1R 特异性 CD8+T 细胞。
从 PBMC 中诱导出了针对三种 MC1R 衍生肽的 CTL，这些肽可以裂解同种异体 HLA-A2+MC1R+黑色素瘤，证明黑色素瘤患者存在抗-MC1R T 细胞库。此外，TIL 也识别 MC1R 表位和 HLA-A2+黑色素瘤细胞系。最后，使用 HLA-A2/MC1R 四聚体鉴定了从 TIL 和亚组 MC1R291 特异性 TIL 中分离出的 HLA-A2/MC1R244 特异性 CD8+T 细胞克隆。
我们的结果表明，MC1R 衍生肽是黑色素瘤特异性 CTL 和 TIL 的常见免疫原性表位，因此可能对开发抗黑色素瘤免疫疗法有用。
