Le cancer du sein, un environnement immunotolérant (émergence, mécanismes d'action des lymphocytes T régulateurs CD4+ CD25+ et relations avec les cellules dendritiques plasmacytoïdes)

Malgré l infiltration des tumeurs de sein par les acteurs du système immunitaire, leur rejet spontané est rarement documenté. Nos travaux sur les lymphocytes T régulateurs CD4+CD25high (Treg), cellules inhibitrice de la réponse immune, pourraient expliquer cette apparente contradiction. En effet, des Treg fonctionnels sont présents en fortes proportions dans les tumeurs primaires de sein et ont un impact négatif sur la survie des patientes. Cet impact sur la survie n est observé que lorsque les Treg sont présents en périphérie de la tumeur dans les agrégats lymphoïdes au contact de cellules dendritiques (DC) matures, où ils sont activés et en prolifération, mais pas lorsqu ils se trouvent dans le lit tumoral. Nous avons par ailleurs démontré le rôle crucial du récepteur CCR4 et d un de ses ligands, CCL22, dans le recrutement des Treg dans la tumeur. Les DC plasmacytoïdes (pDC), cellules productrices d interféron-a du sang lors d infections virales, sont également retrouvées dans les tumeurs de sein et notre équipe a précédemment démontré que leur présence a un impact négatif sur la survie des patientes. Les pDC infiltrant les tumeurs expriment des marqueurs d activation, répondent in vitro à des signaux d activation mais leur capacité à produire de l interféron-a est très fortement altérée. Nous montrons que les cytokines TNF-a et TGF-b produites dans l environnement tumoral sont impliquées dans cette inhibition. Les perspectives de ce travail sont d identifier les mécanismes de suppression utilisées par les Treg ainsi que l importance de leur interaction avec les pDC dans le but de restaurer une réponse immunitaire anti-tumorale effectrice via la neutralisation des Treg et la réactivation des pDC dans les cancers du seinDespite the infiltration of tumors by the immune competent cells, spontaneous rejection of breast tumors is rarely documented. Our work on CD4+CD25high regulatory T cells (Treg), cells inhibiting the immune response, might reconciliate this apparent discrepancy. Indeed, functional Treg are present in high proportions in primary breast tumors and have a negative impact on patient s survival. This negative impact occurs only when Treg are present in the periphery of the tumor in the lymphoid aggregates in contact with mature Dendritic Cells (DC), where they are activated and proliferate, but not in the tumor area. Regarding their intra-tumoral recruitment, we have demonstrated the importance of the CCR4 receptor and one of its ligands CCL22. Plasmacytoid DC (pDC), circulating interferon-a producing cells during viral infection, are also present in breast tumors and their presence has a negative impact on patients survival as previously demonstrated by our team. Tumor-infiltrating pDC express activation markers, respond in vitro to activation signals, but their ability to produce interferon-a is strongly impaired. We showed that two cytokines, TGF-b and TNF-a produced within tumor microenvironment are involved in this inhibition. The perspectives of this work are to identify the mechanisms of Treg mediated suppression and the importance of their interaction with pDC. Our goal is to understand how to neutralize Treg and reactivate pDC in breast cancer in order to restore an anti tumor immune responseLYON1-BU.Sciences (692662101) / SudocSudocFranceF

Insulin-like growth factor (IGF) family and prostate cancer

There is abundant in vitro, animal and epidemiologic evidence to suggest that the Insulin-Like Growth Factor (IGF) family is a multicomponent network of molecules which is involved in the regulation of both physiological and pathological growth processes in prostate. The IGF family plays a key role in cellular metabolism, differentiation, proliferation, transformation and apoptosis, during normal development and malignant growth. This family also seem essential in prostate cancer bone metastases, angiogenesis and androgen-independent progression. Therapeutic alternatives in men with progressive prostate cancer after androgen ablation are very limited. More effective therapies are needed for these patients. Pharmacologic interventions targeting the IGF family are being devised. Such strategies include reduction of IGF-I levels (growth hormone-releasing hormone antagonists, somatostatin analogs), reduction of functional IGF-I receptor levels (antisense oligonucleotides, small interfering RNA), inhibition of IGF-IR and its signalling (monoclonal antibodies, small-molecule tyrosine kinase inhibitors) and Insulin-Like Growth Factor Binding Proteins. (c) 2005 Elsevier Ireland Ltd. All rights reserved

Interleukin-6, Interleukin-10, and Vascular Endothelial Growth Factor in Metastatic Renal Cell Carcinoma: Prognostic Value of Interleukin From the Groupe Français d'Immunothérapie

International audienc

Interleukin-6 Interleukin-10 and Vascular Endothelial Growth Factor in Metastatic Renal Cell Carcinoma: Prognostic Value of Interleukin-6--From the Groupe Français d'Immunothérapie

International audienc

Interleukin-6, Interleukin-10, and Vascular Endothelial Growth Factor in Metastatic Renal Cell Carcinoma: Prognostic Value of Interleukin From the Groupe Français d'Immunothérapie

International audienc

CD4 lymphopenia to identify end-of-life metastatic cancer patients.

International audienceBACKGROUND: Cancer patients with CD4 lymphopenia have an increased risk of severe toxicity after administration of cytotoxic chemotherapy. The impact of CD4 lymphopenia on long term overall survival (OS) of cancer patients was explored in this work. PATIENTS AND METHODS: The first prospective series (test series) included 219 patients with solid tumours, lymphomas or myelomas receiving chemotherapy within an oncology department in 1999 and 2000. A phenotypic analysis of lymphocyte subsets by flow cytometry was performed before chemotherapy on day 1. The prognostic value of total, CD4, CD8 and CD56 lymphocyte count for OS was tested in a multivariate analysis. The prognostic value of low CD4 counts was then tested in a validation series of 269 patients with metastatic solid tumours in second line treatment included in a prospective observational study in the Centre Leon Berard. RESULTS: In the test series, all patients with metastatic cancers and CD4 lymphopenia ≤ 200/μL (12% of metastatic patients) died within 18 months with a median OS of 5.9 months. CD4 count was an independent prognostic factor for OS and PFS in multivariate analysis. In the validation series, 83 (30%) of patients had CD4 count ≤ 200/μL: their median overall survival was 3.9 months with an 18-month survival rate of 6%. CD4 count was also an independent prognostic factor for overall survival in this series. CONCLUSIONS: CD4 lymphopenia <200/μL is frequent in advanced cancer patients and associated with a very short life expectancy. These patients should be proposed for specific treatment and research approaches