Pre-clinical blocking of PD-L1 molecule, which expression is down regulated by NF-κB, JAK1/JAK2 and BTK inhibitors, induces regression of activated B-cell lymphoma

Cell Communication and Signaling

Ursula Zimber-Strobl¹  Lilian Roland²  Jean Feuillard²  Nathalie Faumont²  Christelle Vincent-Fabert² 

[1] Research Unit Gene Vectors, Helmholtz Center Munich, German Research Center for Environmental Health GmbH;UMR-CNRS 7276/INSERM U1262 CRIBL “Contrôle de la Réponse Immune B et Lymphoproliférations”, CBRS “Centre de Biologie et de Recherche en Santé”, Dupuytren Hospital University Center, University of Limoges, Hematology Laboratory of Dupuytren CHU;

关键词: B-cell lymphomas;    PD-L1;    Immune surveillance;   

DOI  :  10.1186/s12964-019-0391-x

来源: DOAJ

【 摘 要 】

Abstract Escape from immune control must be important in the natural course of B-cell lymphomas, especially for those with activation of NF-κB. The pre-clinical LMP1/CD40-expressing transgenic mouse model is characterized by B-cell specific CD40 signaling responsible for NF-κB continuous activation with a spleen monoclonal B-cell tumor after 1 year in 60% of cases. LMP1/CD40 tumors B-cells expressed high levels of PD-L1. This expression was dependent on activation of either NF-κB, JAK1/JAK2 or BTK pathways since these pathways were activated in tumor B-cells and ex vivo treatment with the inhibitory molecules PHA-408, ruxolitinib and ibrutinib led to decrease of its expression. Treatment of LMP1/CD40-expressing lymphomatous mice with an anti-PD-L1 monoclonal antibody induced tumor regression with decreased spleen content, activation and proliferation rate of B-cells as well as a marked increase in T-cell activation, as assessed by CD62L and CD44 expression. These results highlight the interest of therapies targeting the PD-1/PD-L1 axis in activated lymphomas with PD-L1 expression, with possible synergies with tyrosine kinase inhibitors.

【 授权许可】

Unknown