Effect of the BTK inhibitor ibrutinib on macrophage- and γδ T cell-mediated response against Mycobacterium tuberculosis

Abstract

The Bruton’s tyrosine kinase (BTK) inhibitor ibrutinib is approved by the Food and Drug Administration for its use as first-line treatment in chronic lymphocytic leukemia (CLL). Despite its efficacy, patients treated with ibrutinib rarely achieve complete responses and usually remain under treatment until progression. Considering the inherent high susceptibility of CLL patients to infections, a better understanding of ibrutinib effects on the immune system might help to estimate the risk of infectious complications on treated patients. Besides its effects on leukemic B cells, ibrutinib also affects functions on T cells, natural killer cells, and macrophages 1 , 2 , 3 . Macrophages are central players of the innate immune response against fungi, extracellular bacteria, and in particular against the intracellular bacteria Mycobacterium tuberculosis ( Mtb ). The World Health Organization (WHO) estimates that one-third of the world’s population is infected with Mtb , the causing agent of tuberculosis, a severe infection that kills near 1.3 million people per year and the leading cause of death from a single infectious agent (Global TB report, WHO, 2017). Notably, the incidence rate of tuberculosis is highly variable among different countries. In South American countries, such as Argentina and Brazil, where ibrutinib is being introduced, the rates of tuberculosis incidence are up to 14 times higher than in USA and other developed countries. Given the relevance of macrophages in Mtb immune response, we here evaluated the in vitro effects of ibrutinib on this cell compartment. Additionally, we studied its effects on γδ T cells, another innate immune component reported to be involved in Mtb response 4 . Strikingly, we found that ibrutinib affects macrophage's phenotype and the response of both macrophages and γδ T cells to Mtb .