AUTHOR=Chen Yu-Chen Enya , Burgess Melinda , Mapp Sally , Mollee Peter , Gill Devinder , Blumenthal Antje , Saunders Nicholas A. TITLE=SIRPĪ± Suppresses Response to Therapeutic Antibodies by Nurse Like Cells From Chronic Lymphocytic Leukemia Patients JOURNAL=Frontiers in Immunology VOLUME=Volume 11 - 2020 YEAR=2021 URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2020.610523 DOI=10.3389/fimmu.2020.610523 ISSN=1664-3224 ABSTRACT=Antibody therapies improve outcomes for chronic lymphocytic leukemia (CLL) patients. However, resistance often develops. In CLL, resistance to therapeutic antibodies, by monocyte derived macrophages (referred to as nurse like cells, NLCs), is characterised by suppression of antibody dependent phagocytosis (ADP). The mechanism(s) contributing to the muted ADP responses remain unresolved. However, an innate immune checkpoint was recently described that uses the CD47:SIRPalpha axis to suppress phagocytic responses by macrophages. Using siRNA depletion strategies we show that SIRPalphais a suppressor of ADP responses. Moreover, we show that the CD47:SIRPalpha immune checkpoint contributes to the resistance phenotype in NLCs derived from CLL patients. Finally, we show that SIRPalpha suppression is mediated via the phosphatase, Shp1, which in turn suppresses SYK-dependent activation of ADP. Thus, we identify a druggable pathway that could be exploited to enhance sensitivity to existing therapeutic antibodies used in CLL. This is the first study to show that activation of the CD47:SIRPalpha innate immune checkpoint contributes to ADP resistance in NLCs from CLL patients.