Enhancement of tumor-reactive cytotoxic CD4+ T cell responses after ipilimumab treatment in four advanced melanoma patients. uri icon

Overview

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.

publication date

  • October 1, 2013

Research

keywords

  • Antibodies, Monoclonal
  • CD4-Positive T-Lymphocytes
  • Melanoma
  • T-Lymphocytes, Cytotoxic

Identity

PubMed Central ID

  • PMC3861895

Scopus Document Identifier

  • 84906939784

Digital Object Identifier (DOI)

  • 10.1158/2326-6066.CIR-13-0068

PubMed ID

  • 24396833

Additional Document Info

volume

  • 1

issue

  • 4