The Bruton's tyrosine kinase inhibitor ibrutinib exerts immunomodulatory effects through regulation of tumor-infiltrating macrophages

Abstract

The Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has demonstrated promising efficacy in a variety of hematologic malignancies. However, the precise mechanism of action of the drug remains to be fully elucidated. Tumor-infiltrating macrophages presented in the tumor microenvironment have been shown to promote development and progression of B-cell lymphomas through crosstalk mediated by secreted cytokines and chemokines. Because Btk has been implicated in Toll-like receptor (TLR) signaling pathways that regulate macrophage activation and production of proinflammatory cytokines, we investigated the immunomodulatory effects of Btk inhibitor on macrophages. Our results demonstrate that Btk inhibition efficiently suppresses production of CXCL12, CXCL13, CCL19, and VEGF by macrophages. Furthermore, attenuated secretion of homeostatic chemokines from Btk inhibitor-treated macrophages significantly compromise adhesion, invasion, and migration of lymphoid malignant cells and even those not driven by Btk expression. The supernatants from Btk inhibitor-treated macrophages also impair the ability of endothelial cells to undergo angiogenic tube formation. Mechanistic analysis revealed that Btk inhibitors treatment downregulates secretion of homeostatic chemokines and cytokines through inactivation of Btk signaling and the downstream transcription factors, NF-κB, STAT3, and AP-1. Taken together, these results suggest that the encouraging therapeutic efficacy of Btk inhibitor may be due to both direct cytotoxic effects on malignant B cells and immunomodulatory effects on macrophages present in the tumor microenvironment. This novel mechanism of action suggests that, in addition to B-cell lymphomas, Btk inhibitor may also have therapeutic value in lymphatic malignancies and solid tumors lacking Btk expression.

Ibrutinib withdrawal symptoms in patients with Waldenström macroglobulinemia

“…However, recent data demonstrate ibrutinib induces significant suppression of inflammatory cytokines (i.e. TNFα, IL2RA and CXCL13), as well as a downregulatory effect on T-cells and macrophages [9][10][11][12]. It is possible that re-activation of both tumoral and microenvironmental cells during an ibrutinib hold could generate a cytokine release syndrome and cause the withdrawal symptoms reported here.…”

Spebrutinib (CC-292) Affects Markers of B Cell Activation, Chemotaxis, and Osteoclasts in Patients with Rheumatoid Arthritis: Results from a Mechanistic Study

“…CXCL13 is an important mediator of lymphocyte homing to the lymph node, which occurs in a BTK-dependent manner [4]. Ibrutinib has been shown to directly inhibit CXCL13 production by macrophages in vitro [14]. Ibrutinib was shown to reduce blood CXCL13 protein levels in patients with mantle cell lymphoma [11] and Waldenstrom macroglobulinemia; high CXCL13 levels at baseline were associated with major clinical response in patients with Waldenstrom macroglobulinemia [15].…”

The Tumor Microenvironment of DLBCL in the Computational Era

“…In fact, the favorable prognostic value observed for stromal/Mo signatures in DLBCL treated by chemo-immunotherapy may rely on the mechanism of rituximab action, which activates killing by the phagocytic capacity of resident immune cells, especially Mo (53). There is indeed growing interest in exploring the role of pure stromal axes, such as SDF-1/CXCR4, in sustaining B cell survival via BCR-independent mechanisms (54) and affecting their sensitiveness to BCR inhibitors (i.e., ibrutinib) and immune modulators (i.e., lenalidomide) with a known offtarget effect on both the stromal and the immune components of TME (55,56).…”