Peroxisome proliferator-activated receptor alpha deficiency impairs regulatory T cell functions: Possible application in the inhibition of melanoma tumor growth in mice.

6533b7dbfe1ef96bd1270b2e

RESEARCH PRODUCT

Peroxisome proliferator-activated receptor alpha deficiency impairs regulatory T cell functions: Possible application in the inhibition of melanoma tumor growth in mice.

François Ghiringhelli Narcisse Zwetyenga Naim Akhtar Khan Kabirou Moutairou Françoise Salvadori Aziz Hichami Akadiri Yessoufou

subject

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 Perforin MESH: Clonal Anergy biology.protein MESH : Mice Knockout MESH : Animals MESH: Receptors Chemokine CD8 MESH: DNA-Binding Proteins MESH : Immunotherapy Adoptive

description

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.

year	journal	country	edition	language
2016-12-01

https://hal-univ-bourgogne.archives-ouvertes.fr/hal-01452771