University of Pittsburgh Cancer Institute ; Pittsburgh, PA USA ; University of Pittsburgh School of Medicine; Department of Medicine ; Pittsburgh, PA USA.
University of Pittsburgh Cancer Institute ; Pittsburgh, PA USA ; University of Pittsburgh School of Medicine; Department of Immunology ; Pittsburgh, PA USA ; University of Pittsburgh School of Medicine; Department of Dermatology ; Pittsburgh, PA USA.
Oncoimmunology. 2014 Nov 14;3(8):e954501. doi: 10.4161/21624011.2014.954501. eCollection 2014.
A promising vaccine strategy for the treatment of cancer involves the use of vaccines incorporating tumor antigen-derived synthetic peptides that can be coordinately recognized by specific CD4 and CD8 T-cells. Previously, we reported that a MAGE-A6-derived peptide (MAGE-A6) and its highly-immunogenic and cross-reactive homolog derived from HF-2 permease (HF-2) are promiscuously presented by multiple HLA-DR alleles to responder CD4 T-cells obtained from healthy donors and melanoma patients. Here, we investigated whether these same peptides could concomitantly stimulate cross-reactive MAGE-A6-specific CD8 T-cell responses using cells isolated from HLA-A*0201 (HLA-A2) healthy individuals and patients with melanoma. We now show that MAGE-A6 and, even more so, HF-2, induce memory CD8 T cells that recognize HLA-A2 MAGE-A6 tumor target cells. The immunogenicity of these peptides was at least partially attributed to their embedded MAGE-A6 and HF-2 "homologous" sequences. The functional avidity of HF-2 peptide-primed CD8 T cells for the MAGE-A6 peptide was more than 100-fold greater than that of CD8 T cells primed with the corresponding MAGE-A6 peptide. Additionally, these 2 peptides were recognized in interferon γ (IFNγ) and granzyme B ELISPOT assays by CD8 T-cell clones displaying variable T-cell receptor (TCR) Vβ usage. These data suggest that the immune cross-reactivity of the MAGE-A6 and HF-2 peptides extends to CD8 T cells, at least in HLA-A2 donors, and supports the potential translational utility of these epitopes in clinical vaccine formulations and for immunomonitoring of cancer patients.
一种有前景的癌症治疗疫苗策略涉及使用包含肿瘤抗原衍生的合成肽的疫苗，这些肽可以被特定的 CD4 和 CD8 T 细胞协调识别。以前，我们报道了一种 MAGE-A6 衍生肽（MAGE-A6）及其高度免疫原性和交叉反应性同源物来源于 HF-2 透酶（HF-2），可以由多个 HLA-DR 等位基因非特异性呈递给来自健康供体和黑色素瘤患者的应答性 CD4 T 细胞。在这里，我们研究了这些相同的肽是否可以同时刺激交叉反应性 MAGE-A6 特异性 CD8 T 细胞反应，使用从 HLA-A*0201（HLA-A2）健康个体和黑色素瘤患者中分离的细胞。我们现在表明，MAGE-A6，甚至更HF-2，诱导识别 HLA-A2 MAGE-A6 肿瘤靶细胞的记忆 CD8 T 细胞。这些肽的免疫原性至少部分归因于其嵌入的 MAGE-A6 和 HF-2“同源”序列。这些肽引发的 CD8 T 细胞对 MAGE-A6 肽的免疫原性至少比用相应的 MAGE-A6 肽引发的 CD8 T 细胞高 100 倍。此外，干扰素γ（IFNγ）和颗粒酶 B ELISPOT 分析显示，这些 2 种肽被具有可变 T 细胞受体（TCR）Vβ使用的 CD8 T 细胞克隆识别。这些数据表明，MAGE-A6 和 HF-2 肽的免疫交叉反应性至少延伸到 HLA-A2 供体的 CD8 T 细胞，并支持这些表位在临床疫苗制剂和癌症患者免疫监测中的潜在转化应用。
