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

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 L.CD40 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 one year in 60% of cases. L.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 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. 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.

The role of PD-L1 in the immune dysfunction that mediates hypoxia-induced multiple organ injury

“…Moreover, NF-κB, which is strongly activated by the presence of cytokines or bacterial products at the site of inflammation, upregulates the PD-L1 indirectly by promoting the transcription of HIF-1α mRNA [4]. Furthermore, NF-κB can directly regulate the expression of PD-L1 [37]. The overexpression of PD-L1 induced by interferon-γ (IFN-γ) is dependent on NF-κB activity.…”