Peroxisome proliferator-activated receptor alpha deficiency impairs regulatory T cell functions: Possible application in the inhibition of melanoma tumor growth in mice.
Fiche publication
Date publication
décembre 2016
Journal
Biochimie
Auteurs
Membres identifiés du Cancéropôle Est :
Pr GHIRINGHELLI François, Pr ZWETYENGA Narcisse, Pr KAHN Naim, Dr HICHAMI Aziz
Tous les auteurs :
Hichami A, Yessoufou A, Ghiringhelli F, Salvadori F, Moutairou K, Zwetyenga N, Khan NA
Lien Pubmed
Résumé
Regulatory T (Treg) cells are important to induce and maintain immunological self-tolerance. Although the progress accomplished in understanding the functional mechanism of Treg cells, intracellular molecules that control the mechanisms of their suppressive capacity are still on investigation. The present study showed that peroxisome proliferator-activated receptor-alpha deficiency impaired the suppressive activity of Treg cells on CD4(+)CD25(-) and CD8(+) T cell proliferation. In Treg cells, PPARα gene deletion also induced a decrease of migratory abilities, and downregulated the expression of chemokine receptors (CCR-4, CCR-8 and CXCR-4) and p27(KIP1) mRNA. Treg cells from PPARα(-/-) mice also lost their anergic property. Since low Treg activity, as observed in PPARα(-/-) mice, is known to be associated with the inhibition of tumor growth, we inoculated these mice with B16 melanoma cells and assessed tumor proliferation. In PPARα(-/-) mice, cancer growth was significantly curtailed, and it was correlated with high expression of granzyme B and perforin mRNA in tumor bed. Degranulation of cytolytic molecules by CD8(+) T cells, assessed by a perforin-release marker CD107a expression, was higher in PPARα(-/-) mice than that in wild-type mice. Tumor-infiltrating lymphocytes (TIL) in melanoma tumors in PPARα(-/-) mice exhibited high pro-inflammatory Th1 phenotype. Consistently, adoptive transfer into lymphopenic RAG2(-/-) mice of total PPARα(-/-)splenic T cells inhibited more the growth rate of B16 tumor than the wild type splenic T cells. Our findings suggest that PPARα deficiency, by diminishing Treg cell functions and upregulating pro-inflammatory T cell phenotype, exerts an in vivo anti-cancer properties.
Mots clés
Animals, Cell Line, Tumor, Cell Movement, genetics, Cell Proliferation, genetics, Cells, Cultured, Clonal Anergy, genetics, DNA-Binding Proteins, deficiency, Gene Expression Regulation, Neoplastic, Immunotherapy, Adoptive, methods, Male, Melanoma, Experimental, genetics, Mice, Inbred C57BL, Mice, Knockout, PPAR alpha, deficiency, Receptors, Chemokine, genetics, Reverse Transcriptase Polymerase Chain Reaction, T-Lymphocyte Subsets, metabolism, T-Lymphocytes, Regulatory, metabolism, Tumor Burden, genetics
Référence
Biochimie. 2016 Dec;131:1-10