title: Enhancement of tumor-reactive cytotoxic CD4+ T cell responses after ipilimumab treatment in four advanced melanoma patients.
abstract: 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.
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Shigehisa
authors.initials: S
authors.lastname: Kitano
authors.affiliation: Center for Immunotherapy, Roswell Park Cancer Institute, Buffalo, NY 14263.
authors.forename: Takemasa
authors.initials: T
authors.lastname: Tsuji
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Cancer Center, New York, NY 10065 ; Swim Across America Laboratory and Ludwig Institute for Cancer Research, Memorial, Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Caillian
authors.initials: C
authors.lastname: Liu
authors.affiliation: Swim Across America Laboratory and Ludwig Institute for Cancer Research, Memorial, Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Daniel
authors.initials: D
authors.lastname: Hirschhorn-Cymerman
authors.affiliation: Weill Cornell Medical College of Cornell University, New York, NY 10065.
authors.forename: Chrisann
authors.initials: C
authors.lastname: Kyi
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Zhenyu
authors.initials: Z
authors.lastname: Mu
authors.affiliation: Department of Immunology, The University of Texas-MD Anderson Cancer Center, Houston, TX.
authors.forename: James P
authors.initials: JP
authors.lastname: Allison
authors.affiliation: Mount Sinai Icahn School of Medicine, Tisch Cancer Institute, New York, NY 10029.
authors.forename: Sacha
authors.initials: S
authors.lastname: Gnjatic
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Cancer Center, New York, NY 10065.
authors.forename: Jianda D
authors.initials: JD
authors.lastname: Yuan
authors.affiliation: Ludwig Center for Cancer Immunotherapy, Immunology Program, Sloan-Kettering Cancer Center, New York, NY 10065 ; Department of Medicine, Sloan-Kettering Cancer Center, New York, NY 10065 ; Swim Across America Laboratory and Ludwig Institute for Cancer Research, Memorial, Sloan-Kettering Cancer Center, New York, NY 10065 ; Weill Cornell Medical College of Cornell University, New York, NY 10065.
authors.forename: Jedd D
authors.initials: JD
authors.lastname: Wolchok
mesh_terms: D000328:Adult; D000911:Antibodies, Monoclonal / Q000627:therapeutic use*; D000938:Antigen-Presenting Cells / Q000276:immunology; D000951:Antigens, Neoplasm / Q000276:immunology; D015496:CD4-Positive T-Lymphocytes / Q000276:immunology*; D060908:CTLA-4 Antigen / Q000276:immunology; D045744:Cell Line, Tumor; D005260:Female; D053804:Granzymes / Q000276:immunology; D006801:Humans; D007167:Immunotherapy; D000074324:Ipilimumab; D008213:Lymphocyte Activation; D008297:Male; D008545:Melanoma / Q000188:drug therapy*; D008565:Membrane Proteins / Q000276:immunology; D008875:Middle Aged; D054353:Perforin / Q000276:immunology; D020825:T-Box Domain Proteins / Q000276:immunology; D013602:T-Lymphocytes, Cytotoxic / Q000276:immunology*; D000098815:T-bet Transcription Factor
chemical_list: D000911:Antibodies, Monoclonal; D000951:Antigens, Neoplasm; C104948:CTAG1B protein, human; D060908:CTLA-4 Antigen; C556706:CTLA4 protein, human; C491199:EOMES protein, human; D000074324:Ipilimumab; D008565:Membrane Proteins; C510468:PRF1 protein, human; D020825:T-Box Domain Proteins; D000098815:T-bet Transcription Factor; D054353:Perforin; C509213:GZMB protein, human; D053804:Granzymes
keywords: Cytotoxic T lymphocyte antigen-4; NY-ESO-1; antibody; cytotoxic CD4+ T cell; ipilimumab; melanoma