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: Shigehisa Kitano, Takemasa Tsuji, Caillian Liu, Daniel Hirschhorn-Cymerman, Chrisann Kyi, Zhenyu Mu, James P Allison, Sacha Gnjatic, Jianda D Yuan, Jedd D Wolchok
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 1 Issue 4 Pg. 235-44 (Oct 2013) ISSN: 2326-6074 [Electronic] United States
• PMID: 24396833 (Publication Type: Case Reports, Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• Antibodies, Monoclonal
• Antigens, Neoplasm
• CTAG1B protein, human
• CTLA-4 Antigen
• CTLA4 protein, human
• EOMES protein, human
• Ipilimumab
• Membrane Proteins
• PRF1 protein, human
• T-Box Domain Proteins
• T-box transcription factor TBX21
• Perforin
• GZMB protein, human
• Granzymes

Topics

• Adult
• Antibodies, Monoclonal (therapeutic use)
• Antigen-Presenting Cells (immunology)
• Antigens, Neoplasm (immunology)
• CD4-Positive T-Lymphocytes (immunology)
• CTLA-4 Antigen (immunology)
• Cell Line, Tumor
• Female
• Granzymes (immunology)
• Humans
• Immunotherapy
• Ipilimumab
• Lymphocyte Activation
• Male
• Melanoma (drug therapy)
• Membrane Proteins (immunology)
• Middle Aged
• Perforin (immunology)
• T-Box Domain Proteins (immunology)
• T-Lymphocytes, Cytotoxic (immunology)