CD4+T cells play a critical role in the induction and maintenance of anti-tumor responses. In order to develop and optimize immunotherapeutic approaches to stimulate human tumor antigen (TA)-specific CD4+ T cells in vivo, we have previously identified a number of promiscuous MHC class II-restricted epitopes from cancer- germline antigens (CGAs), melanocyte-lineage antigens (MDAs) and overexpressed or universal antigens. We have shown that these epitopes stimulate spontaneous circulating TA-specific CD4+ T cells in peripheral blood lymphocytes (PBLs) of patients with advanced melanoma. Most recently, we have shown that TA-specific CD4+ T cells were either T helper or regulatory T cells (T regs). The goal of this proposal is to expand the functional studies of TA-specific regs isolated from patients with advanced melanoma. This research proposal stems from novel findings that be can be stated as follows: 1) MHC class II epitopes stimulate not only spontaneous Foxp3- T-helper and Foxp3+ T regs but also Foxp3+ T helper and Foxp3- T regs, questioning the reliability of Foxp3 as a marker of T regs in humans;2) in contrast to naturally-occurring CD4+CD25+T regs, TA-specific T regs inhibit TA cross-presentation by DCs and cross-priming of TA-specific CD8+ T cells;3) TA- specific T regs act on autologous B cells to inhibit IgG antibody production and stimulate IL-10 production;4) Immature monocyte-derived DCs (iDCs) generated in an immunosuppressive milieu (IL-10 and TGF-2) can be activated by tumor antigen/antibody immune complexes (TA/Ab IC), promoting TA cross-presentation to CD8+ T cells and CD4+ T-helper functions. Collectively, the data generated in this proposal will develop the knowledge required for the induction of potent TA-specific T-helper responses in vivo in patients with advanced melanoma. They will provide a better understanding of the mechanisms by which TA-specific T regs inhibit cross-presentation/cross-priming by DCs and B cell antibody production. Therefore, they will contribute to the development of strategies aimed at expanding immune responses integrating TA-specific T helper cells, TA- specific CD8+ T cells and antibody responses in patients with melanoma.

Public Health Relevance

The proposed study aims at understanding how regulatory T cells recognizing small fragments of protein specifically expressed by melanoma cells (i.e. epitopes), inhibit immune responses to melanoma. This research project will develop the knowledge required for the implementation of novel active and specific immunotherapies to stimulate potent anti-tumor responses in melanoma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA090360-09
Application #
8230739
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Mccarthy, Susan A
Project Start
2001-04-01
Project End
2014-02-28
Budget Start
2012-03-01
Budget End
2013-02-28
Support Year
9
Fiscal Year
2012
Total Cost
$263,096
Indirect Cost
$89,435
Name
University of Pittsburgh
Department
Internal Medicine/Medicine
Type
Schools of Medicine
DUNS #
004514360
City
Pittsburgh
State
PA
Country
United States
Zip Code
15213
Fourcade, Julien; Sun, Zhaojun; Pagliano, Ornella et al. (2014) PD-1 and Tim-3 regulate the expansion of tumor antigen-specific CD8ýýý 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
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
Raskovalova, Tatiana; Lokshin, Anna; Huang, Xiaojun et al. (2007) Inhibition of cytokine production and cytotoxic activity of human antimelanoma specific CD8+ and CD4+ T lymphocytes by adenosine-protein kinase A type I signaling. Cancer Res 67:5949-56
Wang, Xiao-Fei; Cohen, William M; Castelli, Florence A et al. (2007) Selective identification of HLA-DP4 binding T cell epitopes encoded by the MAGE-A gene family. Cancer Immunol Immunother 56:807-18

Showing the most recent 10 out of 14 publications