There is ample evidence that patients with melanoma can develop immune responses directed against antigens expressed by their own tumor. However, very high frequencies of spontaneous or vaccine-induced tumor antigen (TA)-specific cytotoxic T cells (CTLs) have failed to induce melanoma rejection. Understanding the failure of spontaneous TA-specific T cell responses to promote regression of melanoma is therefore critical for the design of novel therapeutic interventions aimed at overcoming tumor-induced immune escape. Among the numerous mechanisms of tumor-induced immunosuppression that contribute to the resistance of tumors to cytotoxic T cells, a number of experimental studies in animals and in humans have suggested the role of co- inhibitory pathways like programmed death 1 (PD-1)/programmed death ligand 1 (PD-L1) interactions in inhibiting the effector functions of TA-specific CD8+ T cells. Spontaneous TA-specific CD8+ T cells in peripheral blood lymphocytes (PBLs) or tumor-infiltrating lymphocytes (TILs) of patients with advanced melanoma appear to upregulate PD-1 expression. PD-1 is a regulator of TA-specific CD8+ T cell expansion in the context of chronic antigen stimulation. However, PD-1 upregulation alone on spontaneous TA-specific CD8+ T cells is not consistently and directly associated with T cell dysfunction on a cell-per-cell basis. This critical observation raises the hypothesis that the co-expression of multiple co-inhibitory receptors including PD-1 may be expressed by highly dysfunctional/exhausted T cells, as previously observed in virus-specific CD8+ T cells in mice with chronic viral infections. Here, we propose to address this question and investigate whether other co-inhibitory molecular pathways are involved in TA-specific T cell dysfunction in patients with advanced melanoma. We will also investigate whether blockade of these pathways may act synergistically with PD-1/PD-L1 pathway blockade to reverse melanoma-induced T cell dysfunction of TA-specific CD8+ and CD4+ T cells in PBLs and TILs of patients with advanced melanoma. Collectively, the findings derived from the outlined studies will support the use of combinatorial co-inhibitory pathway blockades in immunotherapeutic interventions to reverse tumor-induced T cell exhaustion/dysfunction in patients with advanced melanoma.

Public Health Relevance

The proposed study aims at understanding the failure of T cell immune responses to promote melanoma regression. This research project is therefore critical for the design of novel therapeutic interventions aimed at overcoming tumor-induced immune escape and stimulating potent anti-tumor responses in melanoma patients.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
5R01CA157467-02
Application #
8239513
Study Section
Cancer Immunopathology and Immunotherapy Study Section (CII)
Program Officer
Welch, Anthony R
Project Start
2011-04-01
Project End
2016-03-31
Budget Start
2012-04-01
Budget End
2013-03-31
Support Year
2
Fiscal Year
2012
Total Cost
$314,363
Indirect Cost
$106,863
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; Zarour, Hassane M (2013) Strategies to reverse melanoma-induced T-cell dysfunction. Clin Dermatol 31:251-6
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