Macrophage response to Mycobacterium tuberculosis may be compromised in patients with CLL treated with ibrutinib – presentation at iwCLL

The second session at this year’s iwCLL was titled “Role of Non-Leukemic Cells and the Microenvironment in CLL Development”, and was jointly chaired by Silvia Deaglio (University of Turin, Torino, Italy) and Christopher Pepper (Cardiff University, Wales, UK).

During this session, Mercedes Borge from the National Scientific and Technical Research Council, Buenos Aires, Argentina, gave a talk titled “Effects of ibrutinib on macrophage-polarization and on the immune-response against Mycobacterium tuberculosis.”

Ibrutinib (a BTK inhibitor) is now approved by the US Food and Drug Administration (FDA) as first-line therapy for CLL. Ibrutinib not only effects leukemic B-cells, but has also been reported to effect other cells in the tumor microenvironment and the immune system, macrophages for example (Kohrt et al. 2014; Borge et al. 2015; Fiorcari et al. 2016).

Macrophages are a key component of the innate immune system, defending against pathogens (fungi, extracellular bacteria), but Mycobacterium tuberculosis (Mtb) in particular. Macrophages phagocytose and kill Mtb and also release cytokines (TNF-α) to promote granuloma formation, which prevents the growth and spread of the bacterial infection. It has been reported that patients treated with TNF-α blockers have a 25-fold increased risk of tuberculosis. Moreover, the incidence of tuberculosis differs greatly between countries. Argentina and Brazil, where ibrutinib has recently approved, have higher incidences (up to 12 times) of tuberculosis than in the US.

The work presented during this talk aimed to explore the effect of ibrutinib on macrophage polarization and on the effector response to Mtb.

It has been previously reported that M1 cells are less motile in a 3D environment than M2 cells. Therefore, the group aimed to assess if ibrutinib could affect M1 migration in a 3D matrigel matrix. It was found that ibrutinib increased M1 migration in matrigel compared to control cells.

Additionally, it was found that ibrutinib did not modulate STAT1 (involved in IFN-γ-mediated M1 polarization) or STAT6 (involved in IL-4-mediated M2 polarization) activation during macrophage polarization.

Moreover, it was found that ibrutinib significantly induced release of TNF-α in response to TLR2 and TLR4 stimulation even at low concentrations.

Mercedes Borge summarized her talk with a concise conclusion slide:

  1. Borge M. Effects of ibrutinib on macrophage-polarization and on the immune-response against Mycobacterium tuberculosis. XVII International Workshop on Chronic Lymphocytic Leukemia; 2017 May 12–15; New York, USA.