Modulation of p38 MAPK signaling enhances dendritic cell activation of human CD4+ Th17 responses to ovarian tumor antigen.
The recent finding that Th17 infiltration of ovarian tumors positively predicts patient outcomes suggests that Th17 responses play a protective role in ovarian tumor immunity. This observation has led to the question of whether Th17 cells could be induced or expanded to therapeutic advantage by tumor vaccination. In this study, we show that treatment of ovarian tumor antigen-loaded, cytokine-matured human dendritic cells (DC) with a combination of IL-15 and a p38 MAP kinase inhibitor offers potent synergy in antagonism of CD4(+) Treg induction and redirection toward CD4(+) Th17 responses that correlate with strong CD8(+) cytotoxic T lymphocyte (CTL) activation. Ovarian tumor antigen-specific CD4(+) T cells secrete high levels of IL-17 and show reduced expression of CTLA-4, PD-1, and Foxp3 following activation with IL-15/p38 inhibitor-treated DC. We further show that modulation of p38 MAPK signaling in DC is associated with reduced expression of B7-H1 (PD-L1), loss of indoleamine 2,3-dioxygenase activity, and increased phosphorylation of ERK 1/2 MAPK. These observations may allow the development of innovative DC vaccination strategies to boost Th17 immunity in ovarian cancer patients.
Department of Microbiology and Immunology, University of Arkansas for Medical Sciences, Little Rock, AR 72205, USA. CannonMartin@uams.edu
Martin J
MJ
Cannon
Hannah E
HE
Goyne
Pamela J B
PJ
Stone
Laura J
LJ
Macdonald
Lindsey E
LE
James
Everardo
E
Cobos
Maurizio
M
Chiriva-Internati
D000951:Antigens, Neoplasm / Q000378:metabolism*; D003713:Dendritic Cells / Q000166:cytology / Q000201:enzymology*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D005434:Flow Cytometry / Q000379:methods; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000378:metabolism; D008214:Lymphocytes / Q000166:cytology; D010051:Ovarian Neoplasms / Q000378:metabolism*; D010641:Phenotype; D015398:Signal Transduction; D013602:T-Lymphocytes, Cytotoxic / Q000166:cytology; D058504:Th17 Cells / Q000166:cytology* / Q000378:metabolism; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism*
D000951:Antigens, Neoplasm; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D048051:p38 Mitogen-Activated Protein Kinases