Biology subjects

Alouche, N.

Publications and source records attributed to Alouche, N..

4 recordsLinked to original sources

bioRxiv2025

Targeting CXCR4-expressing TAMs in muscle-invasive bladder cancer to enhance tumor control after immunotherapy

Bladder cancer (BC) is a prevalent malignancy with poor prognosis in advanced stages. While immune checkpoint blockade has revolutionized immunotherapy, its efficacy remains limited for most advanced BC patients. The detailed characterization of BCs tumor microenvironment (TME) is a prerequisite to understand these mechanisms of resistance and to develop new therapeutic strategies. In this study, we used a genetically engineered BC mouse model resistant to anti-PD1 treatment, and BC patient samples, to investigate the evolution of tumor-associated macrophages (TAMs) during BC progression. We identified a subset of pro-tumor TAMs expressing CXCR4, predominantly found in advanced stages of BC-bearing mice and in half of muscle-invasive BC patients from the studied cohort. Interestingly, CXCR4+ TAM-rich regions were associated with CD8 T cell-excluded areas in both mice and patients. Administration of a small molecule CXCR4 inhibitor significantly reduced the number of pro-tumor TAMs within the tumor and markedly prolonged mouse survival. Incorporating this inhibitor into a tri-immunotherapy regimen further enhanced survival, highlighting the potential of targeting multiple pathways to strongly enhance anti-tumor effects and offering new hope for improving immunotherapy in advanced BC.

immunology↗

bioRxiv2022

Malt1-dependent cleavage of Tensin-3 controls B-cell adhesion and lymphomagenesis

The protease Malt1 controls the development and function of lymphocytes and promotes lymphomagenesis by cleaving a limited set of cellular substrates, many of which regulate gene transcription. Here, we report the identification of the integrin-binding scaffold protein Tensin-3 as a Malt1 substrate in activated B cells. B cells expressing a non-cleavable form of Tensin-3 (TNS3-nc) showed normal NF-{kappa}B and JNK transcriptional responses but increased and prolonged integrin-dependent adhesion upon activation. Moreover, mice expressing a non-cleavable form of Tensin-3 displayed reduced antibody production in response to immunization with a T-cell dependent antigen. We also explored the role of Tensin-3 in diffuse large B cell lymphomas and mantle cell lymphomas characterized by constitutive Malt1 activity, which showed strong constitutive Tensin-3 cleavage and a correlating reduction in total Tensin-3 levels. Silencing of Tensin-3 expression in Malt1-driven lymphoma models did not affect cellular proliferation but enhanced the dissemination of xenografted lymphoma cells. Thus, Malt1-dependent Tensin-3 cleavage limits integrin-dependent B-cell adhesion and promotes humoral immune responses and metastatic spreading of B cell lymphomas in a transcription-independent manner.

immunology↗

bioRxiv2022

Plasma cell maintenance and antibody secretion are under the control of Sec22b-mediated regulation of organelle dynamics

Despite the essential role of plasma cells in health and disease, the cellular mechanisms controlling their survival and secretory capacity are still poorly understood. Here, we identified the SNARE Sec22b as a unique and critical regulator of plasma cell maintenance and function. In absence of Sec22b, plasma cells were barely detectable and serum antibody titres were dramatically reduced. Accordingly, Sec22b deficient mice fail to mount a protective immune response. At the mechanistic level, we demonstrated that Sec22b is indispensable for efficient antibody secretion but also for plasma cell fitness through the regulation of the morphology of the endoplasmic reticulum and mitochondria. Altogether, our results unveil a critical role for Sec22b-mediated regulation of plasma cell biology through the control of organelle dynamics.

immunology↗

bioRxiv2019

Cxcr4 desensitization is an essential regulatory mechanism controlling the extra-follicular B cell response.

The signaling axis formed by the chemokine CXCL12 and its receptor CXCR4 plays an important role in B cell development and activation and is finely regulated by a process termed desensitization. Mutations leading to a truncation of the C-terminus tail of CXCR4 and thus to a defective desensitization have been reported in two diseases, a rare immunodeficiency called the WHIM syndrome and a B cell plasmacytoma called Waldenstroms Macroglobulinemia (WM). How CXCR4 desensitization may impact B cell activation in the context of a T-independent extra-follicular response is still unknown. Here using a unique mouse model bearing an orthologous gain of function mutation of Cxcr4 we report that Cxcr4 desensitization is an essential gatekeeper controlling B lymphocyte entry into cycle, plasma cell differentiation, migration and maturation upon Myd88-dependent signaling. Altogether, our results support an essential role for Cxcr4 desensitization in limiting the depth and width of the B cell extra-follicular response and PC development.

immunology↗