Antigen Spreading Contributes to MAGE Vaccination-Induced Regression of Melanoma Metastases

作者：Véronique Corbière, Jacques Chapiro, Vincent Stroobant, Wenbin Ma, Christophe Lurquin, Bernard Lethé, Nicolas van Baren, Benoı̂t J. Van den Eynde, Thierry Boon, Pierre G. Coulie · 发表于：Cancer Research · 年份：2011 · 被引用次数：180 · 研究领域：Immunotherapy and Immune Responses、vaccines and immunoinformatics approaches、CAR-T cell therapy research

A core challenge in cancer immunotherapy is to understand the basis for efficacious vaccine responses in human patients. In previous work we identified a melanoma patient who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with tumor regression after vaccination with melanoma antigens (MAGE). Using a genetic approach including T-cell receptor β (TCRβ) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of TCRβ sequences were found with several of these corresponding to CTL clones specific for nonvaccine tumor antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to tumor-specific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the TCRβ sequence to detect and clone the desired T cells from tumor-infiltrating lymphocytes isolated from the patient. This CD8 clone specifically lysed autologous melanoma cells and displayed HLA-A2 restriction. Its target antigen was identified as the mitochondrial enzyme caseinolytic protease. The target antigen gene was mutated in the tumor, resulting in production of a neoantigen. Melanoma cell lysis by the CTL was increased by IFN-γ treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that tumor rejection effectors in the patient were indeed CTL responding to nonvaccine tumor-specific ant...