PT  - JOURNAL ARTICLE
AU  - Kitano, Shigehisa
AU  - Tsuji, Takemasa
AU  - Liu, Caillian
AU  - Hirschhorn-Cymerman, Daniel
AU  - Kyi, Chrisann
AU  - Mu, Zhenyu
AU  - Allison, James P.
AU  - Gnjatic, Sacha
AU  - Yuan, Jianda D.
AU  - Wolchok, Jedd D.
TI  - Enhancement of Tumor-Reactive Cytotoxic CD4<sup>+</sup> T-cell Responses after Ipilimumab Treatment in Four Advanced Melanoma Patients
AID  - 10.1158/2326-6066.CIR-13-0068
DP  - 2013 Oct 01
TA  - Cancer Immunology Research
PG  - 235--244
VI  - 1
IP  - 4
4099  - http://cancerimmunolres.aacrjournals.org/content/1/4/235.short
4100  - http://cancerimmunolres.aacrjournals.org/content/1/4/235.full
SO  - Cancer Immunol Res2013 Oct 01; 1
AB  - 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 patients with advanced melanoma. Four patients with NY-ESO-1 seropositive melanoma 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 four 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 showed 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. Cancer Immunol Res; 1(4); 235–44. ©2013 AACR.