CD4+ T cells provide help to enhance and sustain cytotoxic CD8+ T cell responses. A direct lytic role for this cell population in mouse models further supports the use of tumor-reactive CD4+ T cells for cancer immunotherapy. CTLA-4 blockade has been shown to expand antigen-specific cytotoxic CD4+ T cells in mouse models. We took advantage of spontaneous immunity to the NY-ESO-1 cancer-testis antigen to investigate quantitative and qualitative changes in antigen-specific CD4+ T cell responses after ipilimumab (anti-CTLA-4 monoclonal antibody) treatment in advanced melanoma patients. Four NY-ESO-1 seropositive melanoma patients were chosen upon the availability of suitable blood specimens for characterizing the functions of NY-ESO-1 antigen-specific CD4+ T cell response by enzyme-linked immunospot (ELISPOT), intracellular cytokine staining (ICS) and cytotoxicity assays. Multiple NY-ESO-1 antigen-specific CD4+ T cell responses with Th1 dominance were induced or enhanced after ipilimumab treatment in peripheral blood in all four patients. NY-ESO-1 antigen-specific CD4+ T cell lines established from all 4 patients after ipilimumab treatment recognized naturally processed NY-ESO-1 protein in antigen-presenting cells, expressed master transcription factor Eomesodermin (Eomes) and secreted perforin and Granzyme B. Finally, we demonstrated that these NY-ESO-1 antigen-specific CD4+ T cell lines directly lysed autologous melanoma cell lines expressing NY-ESO-1 in an MHC class II restricted manner. Our results show that antigen specific cytotoxic CD4+ T cell responses are induced after ipilimumab therapy in human cancer patients. Ipilimumab may induce the expression of lytic granules on antigen specific cytotoxic CD4+ T cells via Eomes, revealing a novel consequence of immunologic checkpoint blockade.
- Received May 31, 2013.
- Revision received August 2, 2013.
- Accepted August 5, 2013.
- Copyright © 2013, American Association for Cancer Research.