1. Peroxisome proliferator-activated receptor alpha deficiency impairs regulatory T cell functions: Possible application in the inhibition of melanoma tumor growth in mice
- Author
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François Ghiringhelli, Narcisse Zwetyenga, Naim Akhtar Khan, Kabirou Moutairou, Françoise Salvadori, Aziz Hichami, Akadiri Yessoufou, Lipides - Nutrition - Cancer (U866) ( LNC ), Université de Bourgogne ( UB ) -Institut National de la Santé et de la Recherche Médicale ( INSERM ) -AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon ( ENSBANA ), Laboratoire de Biochimie et de Biologie Moléculaire (Université d'Abomey Calavi, Cotonou, Bénin) ( LBBM ), Université d'Abomey Calavi, French Ministry of Higher Education and Research, National Cancer Institute (1-23651-07), Lipides - Nutrition - Cancer (U866) (LNC), Institut National de la Santé et de la Recherche Médicale (INSERM)-Université de Bourgogne (UB)-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement, Laboratoire de Biochimie et de Biologie Moléculaire (Université d'Abomey Calavi, Cotonou, Bénin) (LBBM), University of Abomey Calavi (UAC), and Université de Bourgogne (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-AgroSup Dijon - Institut National Supérieur des Sciences Agronomiques, de l'Alimentation et de l'Environnement-Ecole Nationale Supérieure de Biologie Appliquée à la Nutrition et à l'Alimentation de Dijon (ENSBANA)
- Subjects
0301 basic medicine ,Male ,Adoptive cell transfer ,MESH: Tumor Burden ,B16 melanoma tumor ,Melanoma, Experimental ,MESH: T-Lymphocyte Subsets ,CD4(+)CD25(+) regulatory T cells ,Biochemistry ,MESH: Mice, Knockout ,Immunotherapy, Adoptive ,T-Lymphocytes, Regulatory ,PPARα ,MESH : T-Lymphocytes, Regulatory ,Cell Movement ,T-Lymphocyte Subsets ,MESH: Reverse Transcriptase Polymerase Chain Reaction ,MESH : Cell Proliferation ,MESH : Cell Movement ,MESH: Animals ,IL-2 receptor ,MESH: PPAR alpha ,MESH: Cell Movement ,Cells, Cultured ,Mice, Knockout ,MESH : Melanoma, Experimental ,biology ,MESH : Tumor Burden ,Reverse Transcriptase Polymerase Chain Reaction ,MESH : Reverse Transcriptase Polymerase Chain Reaction ,FOXP3 ,hemic and immune systems ,General Medicine ,MESH: Gene Expression Regulation, Neoplastic ,3. Good health ,Tumor Burden ,MESH: Melanoma, Experimental ,DNA-Binding Proteins ,Gene Expression Regulation, Neoplastic ,medicine.anatomical_structure ,MESH: Immunotherapy, Adoptive ,Receptors, Chemokine ,MESH : DNA-Binding Proteins ,MESH: Cells, Cultured ,medicine.medical_specialty ,MESH : Receptors, Chemokine ,MESH: Cell Line, Tumor ,Regulatory T cell ,MESH : Gene Expression Regulation, Neoplastic ,T cell ,MESH : Male ,MESH : PPAR alpha ,chemical and pharmacologic phenomena ,MESH : Mice, Inbred C57BL ,MESH : Clonal Anergy ,03 medical and health sciences ,MESH: Mice, Inbred C57BL ,Internal medicine ,MESH: Cell Proliferation ,Cell Line, Tumor ,MESH : Cells, Cultured ,medicine ,Animals ,[SDV.BBM]Life Sciences [q-bio]/Biochemistry, Molecular Biology ,PPAR alpha ,[ SDV.BBM ] Life Sciences [q-bio]/Biochemistry, Molecular Biology ,Cell Proliferation ,Clonal Anergy ,Perforin ,MESH : Cell Line, Tumor ,MESH: T-Lymphocytes, Regulatory ,Molecular biology ,MESH: Male ,MESH : T-Lymphocyte Subsets ,Granzyme B ,Mice, Inbred C57BL ,030104 developmental biology ,Endocrinology ,MESH: Clonal Anergy ,biology.protein ,MESH : Mice, Knockout ,MESH : Animals ,MESH: Receptors, Chemokine ,CD8 ,MESH: DNA-Binding Proteins ,MESH : Immunotherapy, Adoptive - Abstract
International audience; 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.
- Published
- 2016