HLA-DR expression in melanoma: from misleading therapeutic target to potential immunotherapy biomarker

Since the advent of anti-PD1 immune checkpoint inhibitor (ICI) immunotherapy, cutaneous melanoma has undergone a true revolution with prolonged survival, as available 5-year updates for progression-free survival and overall survival demonstrate a durable clinical benefit for melanoma patients receiving ICI. However, almost half of patients fail to respond to treatment, or relapse sooner or later after the initial response to therapy. Little is known about the reasons for these failures. The identification of biomarkers seems necessary to better understand this resistance. Among these biomarkers, HLA-DR, a component of MHC II and abnormally expressed in certain tumor types including melanoma for unknown reasons, seems to be an interesting marker. The aim of this review, prepared by an interdisciplinary group of experts, is to take stock of the current literature on the potential interest of HLA-DR expression in melanoma as a predictive biomarker of ICI outcome

LAG-3 (une cible thérapeutique dans les pathologies inflammatoires et tumorales cutanées)

PARIS7-Bibliothèque centrale (751132105) / SudocSudocFranceF

Calcium signaling and cell fate: how can Ca (2+)signals contribute to wrong decisions for Chronic Lymphocytic Leukemic B lymphocyte outcome?

International audienceCa (2+)signaling is a key regulator of B lymphocyte cell fate and defects in this signaling pathway have been reported in numerous diseases such as Chronic lymphocytic leukemia (CLL). CLL is a B cell clonal disorder characterized by the accumulation of mature monoclonal CD5 (+)B cells. Although CLL could be considered to be a proliferative disease, most circulating CLL B cells are arrested in the G0 phase of the cell cycle and present both defects in calcium (Ca (2+)) homeostasis and signaling. The Ca (2+)response to antigen ligation is heterogeneous and related, in part, to defects arising from the incapacity to respond to B cell receptor (BCR) engagement (anergy), to the expression of T cell kinases (e.g. Zap70), and to the presence of negative feedback regulation by phosphatases (e.g. SHP-1). Anergic CD5 (+)CLL B cells are characterized by an elevated basal Ca (2+)level, IgM/CD79 downregulation, a constitutive activation of BCR pathway kinases, and an activation of the nuclear factor of activated T cells (NF-AT). Based on the Ca (2+)response, patients are classified into three groups: unresponders, responders with apoptosis, and responders with entry in the cell cycle. Moreover, internal and direct interaction between leukemic BCR-HCDR3 epitopes at the plasma membrane and interaction between Bcl-2 and the IP3-receptor at the endoplasmic reticulum are also suspected to interfere with the intracellular Ca (2+)homeostasis in CLL-B cells. As a whole, the Ca (2+)pathway is emerging to play a key role in malignant CLL-B survival, disease progression, and last but not least, in the therapeutic response

Coupling imaging mass cytometry with Alcian blue histochemical staining for a single-slide approach

International audienceImaging mass cytometry (IMC) is a metal mass spectrometry-based method allowing highly multiplex immunophenotyping of cells within tissue samples. However, some limitations of IMC are its 1-µm resolution and its time and costs of analysis limiting respectively the detailed histopathological analysis of IMC-produced images and its application to small selected tissue regions of interest (ROI) of one to few square millimeters. Coupling on a single-tissue section, IMC and histopathological analyses could permit a better selection of the ROI for IMC analysis as well as co-analysis of immunophenotyping and histopathological data until the single-cell level. The development of this method is the aim of the present study in which we point to the feasibility of applying the IMC process to tissue sections previously Alcian blue-stained and digitalized before IMC tissue destructive analyses. This method could help to improve the process of IMC in terms of ROI selection, time of analysis, and the confrontation between histopathological and immunophenotypic data of cells

Calcium, une nouvelle piste thérapeutique dans la leucémie lymphoïde chronique.

International audienc

Calcium, une nouvelle piste thérapeutique dans la leucémie lymphoïde chronique.

International audienc

Efficient Plasma Cell Differentiation and Trafficking Require Cxcr4 Desensitization

CXCR4 plays a central role in B cell immune response, notably by promoting plasma cell (PC) migration and maintenance in the bone marrow (BM). Gain-of-function mutations in CXCR4 affecting receptor desensitization have been reported in the rare immunodeficiency called WHIM syndrome (WS). Despite lymphopenia, patients mount an immune response but fail to maintain it over time. Using a knockin mouse model phenocopying WS, we showed that, counter-intuitively, a gain of Cxcr4 function inhibited the maintenance of antibody titers after immunization. Although the Cxcr4 mutation intrinsically and locally promoted germinal center response and PC differentiation, antigen-specific PCs were barely detected in the BM, a defect mirrored by early accumulation of immature plasmablasts potentially occupying the survival niches for long-lived PCs. Therefore, fine-tuning of Cxcr4 desensitization is critically required for efficient PC differentiation and maintenance, and absence of such a regulatory process may account for the defective humoral immunity observed in WS patients

Entrée constitutive de calcium dans les lymphocytes B : une nouvelle piste thérapeutique pour la leucémie lymphoïde chronique.

International audienc

Entrée constitutive de calcium dans les lymphocytes B : une nouvelle piste thérapeutique pour la leucémie lymphoïde chronique.

International audienc

MUC1 Mitigates Renal Injury and Inflammation in Endotoxin Induced Acute Kidney Injury by Inhibiting the TLR4-MD2 Axis and Reducing Pro-Inflammatory Macrophages Infiltration

International audienceSepsis is the leading cause of acute kidney injury (AKI) in critical care patients. A cornerstone of sepsis-associated AKI is dysregulated inflammation driven by excessive activation of Toll-like receptor 4 (TLR4) pathway. MUC1, a membrane-bound mucin expressed in both epithelial tubular cells and renal macrophages, has been shown to be involved in the regulation of TLRs. Therefore, we hypothesized that MUC1 could mitigate the renal inflammatory response to TLR4 activation. To test this hypothesis, we used a murine model of endotoxin-induced AKI by intraperitoneal injection of LPS. We showed that Muc1−/− mice have a more severe renal dysfunction, an increased activation of the tissular NF-kB pathway and secreted more pro inflammatory cytokines compare to Muc1+/+ mice. By flow cytometry, we observed that the proportion of M1 (pro-inflammatory) macrophages in the kidneys of Muc1−/− mice was significantly increased. In human and murine primary macrophages, we showed that MUC1 is only induced in M1 type macrophages and that macrophages derived from Muc1−/− mice secreted more pro-inflammatory cytokines. Eventually, in HEK293 cells, we showed that MUC1 cytosolic domain (CT) seems necessary for the negative regulation of TLR4 by proximity ligation assay, MUC1-CT is in close relationship with TLR4 and acts as a competitive inhibitor of the recruitment of MYD88. Overall our results support that in the context of endotoxin-induced AKI, MUC1 plays a significant role in controlling disease severity by regulating negatively the TLR4-MD2 axis