Enhancement of tumor-reactive cytotoxic CD4(+) T-cell responses after ipilimumab treatment in four advanced melanoma patients Journal Article
| Authors: | Kitano, S.; Tsuji, T.; Liu, C.; Hirschhorn-Cymerman, D.; Kyi, C.; Mu, Z.; Allison, J. P.; Gnjatic, S.; Yuan, J. D.; Wolchok, J. D. |
| Article 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 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 T(H)1 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. (C)2013 AACR. |
| Keywords: | protein; antigen; metastatic melanoma; cancer-patients; ny-eso-1; immune-responses; cd8(+); clinical benefit; established melanoma; peptide vaccination |
| Journal Title: | Cancer Immunology Research |
| Volume: | 1 |
| Issue: | 4 |
| ISSN: | 2326-6066 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2013-10-01 |
| Start Page: | 235 |
| End Page: | 244 |
| Language: | English |
| ACCESSION: | WOS:000340030200007 |
| DOI: | 10.1158/2326-6066.CIR-13-0068 |
| PROVIDER: | wos |
| PMCID: | PMC3880021 |
| PUBMED: | 24396833 |
| Notes: | Article -- Source: Wos |
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