The BTK inhibitor acalabrutinib inhibits the expression of PD-L1 on myeloid cells during inflammation.

Acalabrutinib (ACP-196), a second-generation BTK inhibitor, is an FDA-approved drug for the treatment of chronic lymphocytic leukemia (CLL)/small lymphocytic lymphoma (SLL) and mantle cell lymphoma (MCL). Beyond targeting malignant B cells, BTK inhibitors can modulate the abundance and functional properties of certain myeloid cell subsets in patients with CLL or MCL. In this study, we investigated the effects of acalabrutinib on the frequency, number, and phenotype of myeloid cell subsets using a mouse model of chronic inflammation induced by repeated injections of heat-killed Bacillus Calmette-Guérin (BCG). We found that acalabrutinib did not inhibit the expansion of myeloid-derived suppressor cells (MDSCs) or affect macrophage abundance in wild-type (WT) or myeloid cell-specific Traf3-deficient (M-Traf3-/-) mice, a mouse model that exhibits MDSC hyperexpansion during chronic inflammation. Interestingly, acalabrutinib significantly inhibited the expression of the immunoinhibitory ligand PD-L1 on monocytic MDSCs (M-MDSCs), macrophages, and dendritic cells (DCs) in vivo. Using cultured MDSCs and macrophages, we demonstrated that acalabrutinib suppressed Toll-like receptor 4 (TLR4)-induced transcript expression of genes encoding PD-L1 and other immunosuppressive molecules, including IL-10, Cox2, and iNos. Mechanistically, acalabrutinib attenuated TLR4-induced activation of NF-κB and Akt signaling. In summary, acalabrutinib inhibits the expression of PD-L1 and other immunosuppressive mediators in MDSCs and macrophages during inflammatory responses by suppressing TLR-driven signaling pathways. Our findings provide novel mechanistic insights and support a potentially broader therapeutic use of acalabrutinib in infectious and inflammatory diseases.