Statins induce regulatory T cell recruitment via a CCL1 dependent pathway

The statins, a group of inhibitors of the 3-hydroxy-3-methylglutaryl coenzyme A reductase, are reported to influence a variety of immune system activities through 3-hydroxy-3-methylglutaryl coenzyme A reductase-dependent and -independent mechanisms. How statin treatment regulates immune system function in vivo nonetheless remains to be fully defined. We analyzed the immunomodulatory effects of lovastatin in a Candida albicans-induced delayed-type hypersensitivity reaction in mice. In this model, lovastatin administration reduced the acute inflammatory response elicited by C. albicans challenge. This anti-inflammatory activity of lovastatin was associated with a shift from a Th1 to a Th2 immune response, as well as an increase in the percentage of regulatory T cells at the inflammation site and in the regional draining lymph node. The lovastatin-induced increase in regulatory T cells in the inflamed skin was dependent on expression of CCL1, a chemokine that is locally up-regulated by statin administration. The anti-inflammatory effect of lovastatin was abrogated in CCL1-deficient mice. These results suggest that local regulation of chemokine expression may be an important process in statin-induced modulation of the immune system.

Politique étrangère suisse

Le conseiller fédéral Didier Burkhalter a pris la direction du Département fédéral des affaires étrangères (DFAE). – Le parlement a octroyé un crédit de 11.35 milliards de francs pour la coopération internationale 2013-2016. – Le Conseil fédéral a activé la clause de sauvegarde envers les Etats de l’UE-8. – Les questions institutionnelles ont continué à bloquer les relations bilatérales avec l’UE. – L’Allemagne et les Etats-Unis ont maintenu la pression sur la place financière suisse lors des négociations d’accords de double-imposition. – Le peuple a refusé l’initiative de l’ASIN « La parole au peuple ! ». – La Suisse a pris position sur le conflit syrien en instaurant des sanctions contre le régime. – La Suisse a fêté ses 10 ans d’adhésion à l’ONU et a reçu son secrétaire général Ban Ki-Moon. – La Suisse a accueilli à Berne le Prix Nobel de la Paix Aung San Suu Kyi et a ouvert une ambassade au Myanmar.

Groupes sociaux

L’UDC a utilisé les instruments de la démocratie directe en déposant une initiative « contre l’immigration de masse » et en lançant une initiative de mise en œuvre pour faire appliquer sa première initiative « pour le renvoi des étrangers criminels ». – Les tours de vis apportés à la loi sur l’asile ont fait couler beaucoup d’encre. Un référendum a été lancé par les jeunes verts.– Le parlement a tenté de trouver des solutions pour faire face à la pénurie de logements touchant les requérants d’asile.– Avant de passer devant le peuple en 2013, le parlement a arrêté sa position sur le changement constitutionnel demandant un nouvel article sur la famille.– Le Conseil national a accepté de donner le droit aux partenaires de même sexe d’adopter les enfants de leur conjoint.– La politique familiale a été au centre des préoccupations du PDC qui a déposé deux initiatives visant à aider les familles.

Active immunosurveillance in the tumor microenvironment of colorectal cancer is associated with low frequency tumor budding and improved outcome.

Tumor budding (single tumor cells or small tumor cell clusters) at the invasion front of colorectal cancer (CRC) is an adverse prognostic indicator linked to epithelial-mesenchymal transition. This study characterized the immunogenicity of tumor buds by analyzing the expression of the major histocompatibility complex (MHC) class I in the invasive tumor cell compartment. We hypothesized that maintenance of a functional MHC-I antigen presentation pathway, activation of CD8+ T-cells, and release of antitumoral effector molecules such as cytotoxic granule-associated RNA binding protein (TIA1) in the tumor microenvironment can counter tumor budding and favor prolonged patient outcome. Therefore, a well-characterized multipunch tissue microarray of 220 CRCs was profiled for MHC-I, CD8, and TIA1 by immunohistochemistry. Topographic expression analysis of MHC-I was performed using whole tissue sections (n = 100). Kirsten rat sarcoma viral oncogene homolog (KRAS) and B-Raf proto-oncogene, serine/threonine kinase (BRAF) mutations, mismatch repair (MMR) protein expression, and CpG-island methylator phenotype (CIMP) were investigated. Our results demonstrated that membranous MHC-I expression is frequently down-regulated in the process of invasion. Maintained MHC-I at the invasion front strongly predicted low-grade tumor budding (P = 0.0004). Triple-positive MHC-I/CD8/TIA1 in the tumor microenvironment predicted early T-stage (P = 0.0031), absence of lymph node metastasis (P = 0.0348), lymphatic (P = 0.0119) and venous invasion (P = 0.006), and highly favorable 5-year survival (90.9% vs 39.3% in triple-negative patients; P = 0.0032). MHC-I loss was frequent in KRAS-mutated, CD8+ CRC (P = 0.0228). No relationship was observed with CIMP, MMR, or BRAF mutation. In conclusion, tumor buds may evade immune recognition through downregulation of membranous MHC-I. A combined profile of MHC-I/CD8/TIA1 improves the prognostic value of antitumoral effector cells and should be preferred to a single marker approach.