Antigen spreading contributes to MAGE vaccination-induced regression of XXXX metastases.

@entity1 @entity5 @entity11112 @entity405 @entity320
A core challenge in @entity5 immunotherapy is to understand the basis for efficacious vaccine responses in @entity1 @entity1 . In previous work we identified a @entity320 @entity1 who displayed a low-level antivaccine cytolytic T-cell (CTL) response in blood with @entity5 regression after vaccination with @entity320 antigens (MAGE). Using a genetic approach including @entity11112 ( @entity11112 ) cDNA libraries, we found very few antivaccine CTLs in regressing metastases. However, a far greater number of @entity11112 sequences were found with several of these corresponding to CTL clones specific for nonvaccine @entity5 antigens, suggesting that antigen spreading was occurring in regressing metastases. In this study, we found another TCR belonging to @entity5 -specific CTL enriched in regressing metastases and detectable in blood only after vaccination. We used the @entity11112 sequence to detect and clone the desired T cells from @entity5 -infiltrating lymphocytes isolated from the @entity1 . This @entity405 clone specifically lysed autologous @entity320 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 @entity5 , resulting in production of a neoantigen. @entity320 cell lysis by the CTL was increased by IFN-y treatment due to preferential processing of the antigenic peptide by the immunoproteasome. These results argue that @entity5 rejection effectors in the @entity1 were indeed CTL responding to nonvaccine @entity5 -specific antigens, further supporting our hypothesis. Among such antigens, the mutated antigen we found is the only antigen against which no T cells could be detected before vaccination. We propose that antigen spreading of an antitumor T-cell response to truly @entity5 -specific antigens contributes decisively to @entity5 regression.
