Open AccessPB2057 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
Author(s) -
VincentFabert C.,
Roland L.,
ZimberStrobl U.,
Feuillard J.,
Faumont N.
Publication year - 2019
Publication title -
hemasphere
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.677
H-Index - 11
ISSN - 2572-9241
DOI - 10.1097/01.hs9.0000566716.49804.5b
Subject(s) - bruton's tyrosine kinase , cd40 , cancer research , b cell , t cell , cd44 , breakpoint cluster region , immune system , monoclonal antibody , biology , chemistry , tyrosine kinase , microbiology and biotechnology , cell , signal transduction , antibody , immunology , receptor , cytotoxic t cell , in vitro , biochemistry
Background: Escape from immune control must be important in the natural course of B‐cell lymphomas, especially for those with activation of NF‐kB. Aims: To search for PD‐L1 expression in mouse model L.CD40 that could explain the tumor B cells escape of immune surveillance. Methods The pre‐clinical L.CD40 transgenic mouse model is characterized by B‐cell specific CD40 signaling responsible for NF‐kB continuous activation with a spleen monoclonal B‐cell tumor after one year in 60% of cases. L.CD40 mice were injected with anti‐PD‐L1 antibody. Results: L.CD40 tumors B‐cells expressed high levels of PD‐L1. This expression was dependent on activation of either NF‐kB, JAK1/JAK2 or BTK pathways since ex vivo treatment with the inhibitory molecules PHA‐408, ruxolitinib and ibrutinib led to decrease of its expression. Treatment of L.CD40 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. Summary/Conclusion: 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.