Showing papers by "Christophe Caux published in 2012"
TL;DR: Findings indicate that IFN-α-deficient TApDC accumulating in aggressive tumors are involved in the expansion of TATreg in vivo, contributing to tumor immune tolerance and poor clinical outcome, and targeting pDC to restore their IFn-α production may represent an attractive therapeutic strategy to overcome immune tolerance in breast cancer.
Abstract: Infiltration and dysfunction of immune cells have been documented in many types of cancers. We previously reported that plasmacytoid dendritic cells (pDC) within primary breast tumors correlate with an unfavorable prognosis for patients. The role of pDC in cancer remains unclear but they have been shown to mediate immune tolerance in other pathophysiologic contexts. We postulated that pDC may interfere with antitumor immune response and favor tolerance in breast cancer. The present study was designed to decipher the mechanistic basis for the deleterious impact of pDC on the clinical outcome. Using fresh human breast tumor biopsies ( N = 60 patients), we observed through multiparametric flow cytometry increased tumor-associated (TA) pDC (TApDC) rates in aggressive breast tumors, i.e., those with high mitotic index and the so-called triple-negative breast tumors (TNBT). Furthermore, TApDC expressed a partially activated phenotype and produced very low amounts of IFN-α following toll-like receptor activation in vitro compared with patients9 blood pDC. Within breast tumors, TApDC colocalized and strongly correlated with TA regulatory T cells (TATreg), especially in TNBT. Of most importance, the selective suppression of IFN-α production endowed TApDC with the unique capacity to sustain FoxP3 + Treg expansion, a capacity that was reverted by the addition of exogenous IFN-α. These findings indicate that IFN-α–deficient TApDC accumulating in aggressive tumors are involved in the expansion of TATreg in vivo , contributing to tumor immune tolerance and poor clinical outcome. Thus, targeting pDC to restore their IFN-α production may represent an attractive therapeutic strategy to overcome immune tolerance in breast cancer. Cancer Res; 72(20); 5188–97. ©2012 AACR .
258 citations
TL;DR: It is shown that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells, and strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer.
Abstract: Human breast tumors are infiltrated by memory CD4(+) T cells along with increased numbers of regulatory T cells (Treg) and plasmacytoid dendritic cells (pDC) that facilitate immune escape and correlate with poor prognosis. Here, we report that inducible costimulatory molecule (ICOS), a T cell costimulatory molecule of the CTLA4/PD1/CD28 family, is expressed mostly by tumor-associated Treg in primary breast tumors. A large proportion of these ICOS(+) Treg were Ki67(+) and this evident proliferative expansion was found to rely on interactions with tumor-associated pDC. Indeed, tumor-associated Treg highly expanded in presence of pDC but failed to proliferate under CD3/CD28 signal. In vitro experiments revealed that the addition of a neutralizing anti-ICOS antibody blocked pDC-induced Treg expansion and interleukin-10 secretion by memory CD4(+) T cells, establishing a pivotal role for ICOS in this process. Supporting these findings, the presence of ICOS(+) cells in clinical specimens of breast cancer correlated with a poor prognosis. Together, our results highlight an important relationship between Treg and pDC in breast tumors, and show that ICOS/ICOS-L interaction is a central event in immunosuppression of tumor-associated memory CD4(+) T cells. These findings strongly rationalize antibody-mediated ICOS blockade as a powerful clinical strategy to correct immune escape and promote therapeutic responses in breast cancer.
185 citations
TL;DR: It was found that accumulation of plasmacytoid dendritic cells in tumors is associated with early relapse and this deleterious effect of tumor-associated pDC was evident when they are present in cancer epithelium but not in lymphoid aggregates.
Abstract: Using two different and complementary approaches (flow cytometry and immunohistochemistry) on two independent cohorts of ovarian cancer patients, we found that accumulation of plasmacytoid dendritic cells (pDC) in tumors is associated with early relapse. This deleterious effect of tumor-associated pDC was evident when they are present in cancer epithelium but not in lymphoid aggregates.
113 citations
TL;DR: This review discusses the balance between the intrinsic activation of PRR in tumor cells and the extrinsic microenvironment activation in term of overall effect ofPRR ligands on tumor development and reviews recent advances in the field.
Abstract: Pattern recognition receptors (PRRs) are known for many years for their role in the recognition of microbial products and the subsequent activation of the immune system. The 2011 Nobel Prize for medicine indeed rewarded J. Hoffmann/B. Beutler and R. Steinman for their revolutionary findings concerning the activation of the immune system, thus stressing the significance of understanding the mechanisms of activation of the innate immunity. Such immunostimulatory activities are of major interest in the context of cancer to induce long-term antitumoral responses. Ligands for the toll-like receptors (TLRs), a well-known family of PRR, have been shown to have antitumoral activities in several cancers. Those ligands are now undergoing extensive clinical investigations both as immunostimulant molecules and as adjuvant along with vaccines. However, when considering the use of these ligands in tumor therapy, one shall consider the potential effect on the tumor cells themselves as well as on the entire organism. Recent data indeed demonstrate that TLR activation in tumor cells could trigger both pro- or antitumoral effect depending on the context. This review discusses this balance between the intrinsic activation of PRR in tumor cells and the extrinsic microenvironment activation in term of overall effect of PRR ligands on tumor development. We review recent advances in the field and underline appealing prospects for clinical development of PRR agonists in the light of our current knowledge on their expression and activation.
103 citations
TL;DR: Lympho-divpenia was found to be an independent prognostic factor in the pooled cohort along with lack of HER2 and hormonal receptors expression and anemia and was used to improve quality of MBC patients’ medical care.
Abstract: Lymphopenia (< 1Giga/L) detected before initiation of chemotherapy is a predictive factor for death in metastatic solid tumors. Combinatorial T cell repertoire (TCR) diversity was investigated and tested either alone or in combination with lymphopenia as a prognostic factor at diagnosis for overall survival (OS) in metastatic breast cancer (MBC) patients. The combinatorial TCR diversity was measured by semi quantitative multi-N-plex PCR on blood samples before the initiation of the first line chemotherapy in a development (n = 66) and validation (n = 67) MBC patient cohorts. A prognostic score, combining lymphocyte count and TCR diversity was evaluated. Univariate and multivariate analyses of prognostic factors for OS were performed in both cohorts. Lymphopenia and severe restriction of TCR diversity called "divpenia" (diversity ≤ 33%) were independently associated with shorter OS. Lympho-divpenia combining lymphopenia and severe divpenia accurately identified patients with poor OS in both cohorts (7.6 and 10.6 vs 24.5 and 22.9 mo). In multivariate analysis including other prognostic clinical factors, lympho-divpenia was found to be an independent prognostic factor in the pooled cohort (p = 0.005) along with lack of HER2 and hormonal receptors expression (p = 0.011) and anemia (p = 0.009). Lympho-divpenia is a novel prognostic factor that will be used to improve quality of MBC patients' medical care.
97 citations
TL;DR: Treg depletion improves endogenous antitumor immunity and the efficacy of active immunotherapy in animal models for cancer, suggesting that inhibiting Treg function could also improve the limited successes of human cancer immunotherapy.
Abstract: Cancers express tumor-associated antigens that should elicit immune response to antagonize the tumor growth, but spontaneous immune rejection of established cancer is rare, suggesting an immunosuppressive environment hindering host antitumor immunity. Among the specific and active tumor-mediated mechanisms, CD4+CD25high T regulatory cells (Treg) are important mediators of active immune evasion in cancer. In this review, we will discuss Treg subpopulations and the mechanisms of their suppressive functions. Treg depletion improves endogenous antitumor immunity and the efficacy of active immunotherapy in animal models for cancer, suggesting that inhibiting Treg function could also improve the limited successes of human cancer immunotherapy. We will also discuss specific strategies for devising effective cancer immunotherapy targeting Treg.
82 citations
TL;DR: The mechanisms involved in the CCL22 production by breast epithelial tumor cells are deciphered and the major role of their innate immune recognition in this production is proposed.
Abstract: Regulatory T cells (Treg) have been reported of poor prognosis for overall survival in primary breast tumors (BT). As CCL22 plays a major role in Treg recruitment within primary BT we deciphered the mechanisms involved in the CCL22 production by breast epithelial tumor cells and propose herein the major role of their innate immune recognition in this production.
25 citations
TL;DR: Until recently, cancer therapy was limited to “debulking approaches” including surgery, chemo–radio- and hormono-therapy and compounds targeting oncogenes or proangiogenic pathways, suggesting that long-term protective effects were not achieved.
Abstract: Until recently, cancer therapy was limited to “debulking approaches” including surgery, chemo–radio- and hormono-therapy and compounds targeting oncogenes or proangiogenic pathways. Unfortunately, phase III studies pointed out that such strategies, remarkable against primary tumors, mostly affected time to progression but rarely overall survival, suggesting that long-term protective effects were not achieved. Immunotherapy which has long been opposed to chemotherapy because of its susceptibility to drug-induced apoptosis and its lack of efficacy to immediately “debulk,” comes of age for a main reason: immunotherapy may be the sole approach to elicit cancer-specific adaptive immune responses and long-term protection against metastases. Can it be any cure without the involvement of the immune system?
8 citations
06 Jun 2012
TL;DR: In this paper, the authors demonstrate the application of Cognitive Reliability and Error Analysis Method (CREAM) in manual assembly and highlight the main cognitive errors, their impacts and elicit these errors quantitatively.
Abstract: Uncertainties in production and assembly processes have a significant influence on performance. When one speaks about uncertainties, in most of the cases it implies machine breakdowns, defective items or different uncertainties in procurement. However, especially in manual production, each realistic model should also take into account and treat human related uncertainties. Unfortunately, in contrast to "standard" uncertainties, there are no statistical data credible enough to use in order to model them. In the present paper we demonstrate the application of Cognitive Reliability and Error Analysis Method (CREAM) in manual assembly. Through the knowledge of experts Cream permit to highlight the main cognitive errors, their impacts and to elicit these errors quantitatively.
6 citations
TL;DR: In this issue of Blood, Yang et al have demonstrated that the therapeutic activity of a targeted therapy, the tyrosine kinase inhibitor (TKI) dasatinib, unexpectedly depends on antitumor T-cell responses that are strongly potentiated by immunostimulation.
TL;DR: The major needs in terms of scientific research dedicated to gynecologic cancers in the biologic, epidemiology, human and sociologic fields are reported.
Abstract: Each year, 13,000 newly gynecologic cancers are diagnosed in France. Gynecologic cancers were specifically heterogeneous (localisations, histologic subgroups, age class, etc). This work was delineated for a national call dedicated to gynecologic cancers. This review reports the major needs in terms of scientific research dedicated to gynecologic cancers in the biologic, epidemiology, human and sociologic fields. For example, medico-economic strategies adapted to ethnosociologic context, specifically for cervix cancer, took important part of the epidemiologic research. Impact of gynecologic cancer in terms of symptoms and late effects, quality of life after treatments and fertility needs to be specifically explored. For fundamental research, molecular characterisation, biologic markers, impact of immunology and genetics represent the major part of the field need to be explored. Finally, therapeutic and diagnosis innovations, optimization of treatments strategies and development of predictive models in order to perform individual prediction taking into account several risk factors (clinical and molecular) to offer help in management of gynecologic cancers are required.
TL;DR: It is suggested that ICOS represents a therapeutic target in breast cancer that may allow to restore anti-tumor immunity and targeting ICOS with a neutralizing antibody suppresses Ta-Treg proliferation as well as IL-10 secretion in pDC/CD4+ T cell co-culture.
Abstract: Tumor immunosubversion occurs through various mechanisms including the selective recruitment of CD4+ regulatory T cell (Treg) and the alteration of dendritic cell (DC) physiology. We reported that the presence of high number of both Treg and/or plasmacytoid DC (pDC) correlates with poor prognosis in breast (1-2) and ovarian carcinoma (3). We previously demonstrated that CCR4+ Treg are recruited from the periphery to the breast tumor through CCL22 production by breast tumor cells under exposure to IFNg, IL-1b and TNFa, consecutively to Macrophages and Natural killer cell detection of transformed cells (4). We report here that Tumor-associated Treg (Ta-Treg) are highly activated (GITRhighHLA-DRhighCD39high) and show a selective expression of high levels of ICOS, proliferate in situ (Ki-67+) but unlike blood Treg, did not proliferate ex vivo under CD3/CD28 co-stimulation in presence of IL-2. On the other hand, Ta-pDC expressed a partially activated phenotype but lacked their principal function, i.e., their type-I interferon production (key mediator of antiviral and tumoral immune responses), is strongly impaired. We show that Ta-Treg and Ta-pDC colocalize within lymphoid structures in vivo and demonstrate the unique capacity of Ta-pDC to favour proliferation of Ta-Treg and CD4+ T cells secreting IL-10. Of importance, this Treg amplification is strongly reduced by addition of exogenous IFNa. Furthermore, targeting ICOS with a neutralizing antibody suppresses Ta-Treg proliferation as well as IL-10 secretion in pDC/CD4+ T cell co-culture, demonstrating a role of ICOS-ICOS-L interaction in Ta-Treg proliferation mediated by Ta-pDC. In contrast, blocking ICOS does not impact T cell responses induced by mDC that, contrary to pDC, do not support Treg enrichment or high IL-10 secretion. Altogether these observations suggest that ICOS represents a therapeutic target in breast cancer that may allow to restore anti-tumor immunity. Grant supports: BCRF, Ligue nationale contre le cancer, ARC, Comite departementaux de la Ligue contre le cancer, INCa. 1. Treilleux I, Blay JY, Bendriss-Vermare N, et al. Dendritic cell infiltration and prognosis of early stage breast cancer. Clin Cancer Res. 2004; 10:7466-74. 2. Gobert M.., Caux C., Blay JY. and Menetrier-Caux C. Treg recruited through CCL22/CCR4 are selectively activated in lymphoid infiltrates surrounding primary breast tumors and lead to an adverse clinical outcome. Cancer Research 2009; 69:2000-9. 3. Labidi-Galy SI, Ray-Coquard I, Menetrier-Caux C, Caux C, Blay JY and Bendriss-Vermare N. Systemic and local dysfunctions of pDC in ovarian carcinoma could contribute to immune tolerance. Cancer Res. 2011; 71:5423-34 4. Faget J., Blay J.Y., Caux C. and Menetrier-Caux C. Early detection of tumor cells by innate immune cells leads to Treg recruitment through CCL22 production by tumor cells. Cancer Res. 2011; 71:6143-52 Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5402. doi:1538-7445.AM2012-5402
01 Jan 2012
01 Jan 2012
TL;DR: A conceptual framework for imperfect data characterizing and modelling is proposed to provide a decision tool to help users to choose the most suitable modelling approach for their manufacturing system problems.
01 Jan 2012
Patent•
29 Mar 2012
TL;DR: In this article, the authors present an invention that concerne des anticorps diriges contre l'ICOS ou un derive de celui-ci qui neutralisent l'engagement d'ICos sur Treg en inhibant la fixation entre LICOS et l'IOCOS-L and abroge the proliferation de Treg induite par les cellules dendritiques plasmacytoides.
Abstract: La presente invention concerne des anticorps diriges contre l'ICOS ou un derive de celui-ci qui neutralisent l'engagement d'ICOS sur Treg en inhibant la fixation entre l'ICOS et l'ICOS-L et abroge la proliferation de Treg induite par les cellules dendritiques plasmacytoides. La presente invention concerne en outre des anticorps diriges contre l'ICOS ou un derive de celui-ci qui induisent la production de l'IL-10 et l'IFNγ, induisent la proliferation des cellules T CD4+, reduisent la proliferation de Tconv, et augmentent la fonction immunosuppressive de Treg.