Myeloid-Derived Suppressor Cells Express Bruton's Tyrosine Kinase and Can Be Depleted in Tumor-Bearing Hosts by Ibrutinib Treatment

Abstract

Myeloid-derived suppressor cells (MDSCs) are a heterogeneous group of immature myeloid cells that expand in tumor bearing hosts in response to soluble factors produced by tumor and stromal cells. MDSC expansion has been linked to loss of immune effector cell function and reduced efficacy of immune-based cancer therapies, highlighting the MDSC population as an attractive therapeutic target. Ibrutinib, an irreversible inhibitor of Bruton’s tyrosine kinase (BTK) and IL2-inducible T-cell kinase (ITK), is in clinical use for the treatment of B cell malignancies. Here, we report that BTK is expressed by murine and human MDSCs, and that ibrutinib is able to inhibit BTK phosphorylation in these cells. Treatment of MDSCs with ibrutinib significantly impaired nitric oxide production and cell migration. In addition, ibrutinib inhibited in vitro generation of human MDSCs and reduced mRNA expression of indolamine 2,3-dioxygenase, an immunosuppressive factor. Treatment of mice bearing EMT6 mammary tumors with ibrutinib resulted in reduced frequency of MDSCs in both the spleen and tumor. Ibrutinib treatment also resulted in a significant reduction of MDSCs in wildtype mice bearing B16F10 melanoma tumors, but not in X-linked immunodeficiency mice (XID) harboring a BTK mutation, suggesting that BTK inhibition plays an important role in the observed reduction of MDSCs in vivo. Finally, ibrutinib significantly enhanced the efficacy of anti-PD-L1 (CD274) therapy in a murine breast cancer model. Together, these results demonstrate that ibrutinib modulates MDSC function and generation, revealing a potential strategy for enhancing immune-based therapies in solid malignancies.

Ibrutinib Inhibits ERBB Receptor Tyrosine Kinases and HER2-Amplified Breast Cancer Cell Growth

“…Sagiv-Barfi and colleagues (16) demonstrated that ibrutinib in combination with anti-PD-L1 antibody provoked strong host T-cell-mediated antitumor activity against various tumor types, including triple-negative breast cancer, which led to high response rates and suppression of metastases. Others have reported ibrutinib modulation via BTK inhibition of myeloid-derived suppressor (17) or mast cells (18) in various solid tumor models. Our enzymatic and cellular assays indicated that the potential for such activities based on ITK and BTK inhibition were relatively unique for ibrutinib compared with other ERBB kinase family inhibitors studied.…”

“…Ibrutinib in combination with anti-PD-L1 antibody was shown to provoke strong host T-cell-mediated antitumor activity against various tumor types (16). Inhibition of BTK by ibrutinib has been suggested to be beneficial in some models by modulating myeloid-derived suppressor cells (17) and mast cells (18). Thus, if ibrutinib has clinically meaningful HER2-targeting activity, its effectiveness could be augmented by such modulation of the tumor microenvironment.…”

The Role of Myeloid-Derived Suppressor Cells in Viral Infection

“…The clinically approved cancer therapeutics ibrutinib and sunitinib inhibited tyrosine kinases present in MDSCs and prevented MDSC generation, migration, and function in several murine tumor models (64,145).…”

Emerging role of BCR signaling inhibitors in immunomodulation of chronic lymphocytic leukemia

“…89 In addition, in a report from Stiff et al on the effects of ibrutinib treatment on MDSCs, which express BTK, ibrutinib inhibited BTK phosphorylation. 90 Together with reduced cell migration and inhibition of in vitro MDSC generation, ibrutinib treatment also reduced MDSCs in spleen and EMT6 murine mammary tumors. Further, ibrutinib treatment reduced MDSCs in a melanoma model in a BTK-dependent fashion.…”