There is accumulating evidence that CD4+ T cells or ?helper? T cells play critical roles in the induction and maintenance of anti-tumor responses. Few class II-restricted melanoma epitopes recognized by CD4+ T cells have been thus far reported and no immunotherapeutic approach has yet been developed successfully in order to generate and stimulate anti-tumor CD4+ T cells in humans. CD4+ T cells recognize tumor epitopes presented by class II molecules at the surface of the melanoma cells or antigen presenting cells. The definition of such epitopes is of major importance because it will allow the development of new vaccine trials designed to induce anti-tumor responses, which are measurable, by precise assays in vivo. We have recently been successful in identifying novel class II-restricted melanoma epitopes and have established experimental strategies that will allow us in the near future to identify other novel epitopes. Our long-term goal is to develop the knowledge required for the optimization of peptide vaccines in order to induce antitumor T cell responses in vivo. This application focuses on determining the best peptide sequences capable of stimulating specific high-avidity melanoma-reactive CD4+ T cells.
The specific Aims are (1) To identify MHC Class II-restricted epitopes encoded by the NY-ESO-1 gene and recognized by Th1- type CD4+ T cells generated from peripheral blood lymphocytes (PBL) of patients with melanoma; (2) To isolate and characterize the Th2 and Th0-type CD4+ T cells that recognize the NY-ESO-1 derived epitopes (3) To identify peptide analogues based on amino acid (aa) substitutions of the original sequence in order to enhance antigen recognition, and dissect the induction of tumor-reactive CD4+ T cell activation events; Using these tools, we will be prepared to prospectively analyze the CD4+ T cell immune responses of patients with melanoma or other NY-ESO-1-expressmg tumors and to use the epitopes to be identified as vaccine components in inimunotherapeutic protocols. Taken together, these data will allow us to better understand the role of ?helper? T cells in the anti-tumor responses in vivo and to design more effective immunotherapeutic clinical protocols based on the modulation of patients responses to such epitopes in vivo.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090360-04
Application #
6910676
Study Section
Experimental Therapeutics Subcommittee 1 (ET)
Program Officer
Yovandich, Jason L
Project Start
2002-07-11
Project End
2007-06-30
Budget Start
2005-07-01
Budget End
2006-06-30
Support Year
4
Fiscal Year
2005
Total Cost
$264,330
Indirect Cost
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Chauvin, Joe-Marc; Pagliano, Ornella; Fourcade, Julien et al. (2015) TIGIT and PD-1 impair tumor antigen-specific CD8? T cells in melanoma patients. J Clin Invest 125:2046-58
Fourcade, Julien; Sun, Zhaojun; Pagliano, Ornella et al. (2014) PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8? T cells induced by melanoma vaccines. Cancer Res 74:1045-55
Fourcade, Julien; Sun, Zhaojun; Pagliano, Ornella et al. (2012) CD8(+) T cells specific for tumor antigens can be rendered dysfunctional by the tumor microenvironment through upregulation of the inhibitory receptors BTLA and PD-1. Cancer Res 72:887-96
Kirkwood, John M; Butterfield, Lisa H; Tarhini, Ahmad A et al. (2012) Immunotherapy of cancer in 2012. CA Cancer J Clin 62:309-35
Kudela, Pavol; Sun, Zhaojun; Fourcade, Julien et al. (2011) Epitope hierarchy of spontaneous CD4+ T cell responses to LAGE-1. J Immunol 186:312-22
Fourcade, Julien; Sun, Zhaojun; Benallaoua, Mourad et al. (2010) Upregulation of Tim-3 and PD-1 expression is associated with tumor antigen-specific CD8+ T cell dysfunction in melanoma patients. J Exp Med 207:2175-86
Fourcade, Julien; Sun, Zhaojun; Kudela, Pavol et al. (2010) Human tumor antigen-specific helper and regulatory T cells share common epitope specificity but exhibit distinct T cell repertoire. J Immunol 184:6709-18
Fourcade, Julien; Kudela, Pavol; Sun, Zhaojun et al. (2009) PD-1 is a regulator of NY-ESO-1-specific CD8+ T cell expansion in melanoma patients. J Immunol 182:5240-9
Fourcade, Julien; Kudela, Pavol; Andrade Filho, Pedro A et al. (2008) Immunization with analog peptide in combination with CpG and montanide expands tumor antigen-specific CD8+ T cells in melanoma patients. J Immunother 31:781-91
Kudela, Pavol; Janjic, Bratislav; Fourcade, Julien et al. (2007) Cross-reactive CD4+ T cells against one immunodominant tumor-derived epitope in melanoma patients. J Immunol 179:7932-40

Showing the most recent 10 out of 16 publications