Activation of Fc Gamma Receptor-Dependent Responses to Therapeutic Antibodies by Nurse Like Cells Requires PI3Kdelta

There is a continued reliance on antibody therapies for treating chronic lymphocytic leukaemia (CLL). Whilst the inclusion of antibody therapies in many standard treatment regimes results in good outcomes, acquired resistance remains a significant clinical challenge for many CLL patients resulting in insensitivity to the antibody treatment. Thus, understanding the mechanisms driving treatment resistance is likely to lead to therapies to reverse resistance and improve patient outcomes. Earlier studies from our laboratory have shown that resistance to therapeutic antibodies, in CLL, is due to a reduced ability of monocyte derived macrophages (MDMs) to participate in FcγR-dependent antitumour responses (e.g. ADCC and antibody-dependent phagocytosis (ADP). In this regard, we recently showed that SYK and BTK activation are downstream of the FcγRs (Oncogene, 36(17):2366-2376, 2017). Moreover, we showed that signalling through the FcγR pathway was reduced in antibody-resistant MDMs and could be reversed using inhibitors of SHIP1. These studies indicated that knowledge of FcγR signalling could exploited to reverse resistance. Unfortunately, knowledge of the exact signalling events controlling FcγR activity in MDMs from CLL patients is unclear.