- Acute myeloid leukemia (AML) is characterized by the proliferation of immature myeloid lineage blasts. Due to its heterogeneity and to the high rate of acquired drug resistance and relapse, new treatment strategies are needed. Here, we demonstrate that IFNγ promotes AML blasts to act as effector cells within the context of antibody therapy. Treatment with IFNγ drove AML blasts toward a more differentiated state, wherein they showed increased expression of the M1-related markers HLA-DR and CD86, as well as of FcγRI, which mediates effector responses to therapeutic antibodies.
- Nurse-like cells (NLCs) play a central role in chronic lymphocytic leukemia (CLL) because they promote the survival and proliferation of CLL cells. NLCs are derived from the monocyte lineage and are driven toward their phenotype via contact-dependent and -independent signals from CLL cells. Because of the central role of NLCs in promoting disease, new strategies to eliminate or reprogram them are needed. Successful reprogramming may be of extra benefit because NLCs express Fcγ receptors (FcγRs) and thus could act as effector cells within the context of antibody therapy.
- The irreversible Bruton's tyrosine kinase (Btk) inhibitor ibrutinib has shown efficacy against B-cell tumors such as chronic lymphocytic leukemia and B-cell non-Hodgkin lymphoma. Fcγ receptors (FcγR) on immune cells such as macrophages play an important role in tumor-specific antibody-mediated immune responses, but many such responses involve Btk. Here we tested the effects of ibrutinib on FcγR-mediated activities in monocytes. We found that ibrutinib did not affect monocyte FcγR-mediated phagocytosis, even at concentrations higher than those achieved physiologically, but suppressed FcγR-mediated cytokine production.
- Background: ITK and RLK are unique to effector lymphocytes and critical for immune activation.Results: A novel selective covalent ITK/RLK inhibitor called PRN694 was discovered, which blocks T-cell and NK cell activation.Conclusion: PRN694 provides an effective tool to elucidate the roles of ITK and RLK in immune cell signaling.Significance: PRN694 could be an effective therapy for T-cell- or NK cell-driven autoimmune, inflammatory, and malignant diseases.