Chen YCE
University of Queensland Diamantina Institute, Australia
Title: Activation of FcγR-dependent responses to therapeutic antibodies by Nurse Like cells requires PI3Kδ
Biography
Biography: Chen YCE
Abstract
Antibody therapies for treating chronic lymphocytic leukaemia (CLL) remain a challenge for many CLL patients who are insensitive to antibody treatment. A high percentage of CLL patients that are resistant to the current combination therapy of chemotherapeutics and immune-therapeutics has always been a clinical challenge. Understanding the mechanisms driving disease progression and treatment resistance is key to improving patient outcomes. Many studies including our own laboratories have shown that resistance to therapeutic antibodies against CLL is due to the survival signals from the monocyte derived macrophages (MDMs), and also an acquired resistance of monocyte derived macrophages to participate in FcγR-dependent antitumour responses. However, the FcγR-dependent signalling pathway in macrophages has not been well studied. Our recently published data suggested that SYK and BTK are involved downstream of FcγR-dependent signalling pathway (referred to as ITAM; Oncogene, 36(17):2366-2376, 2017). In this study we investigate the involvement of PI3K isoforms as they have been known to be an important pathway regulator for cellular function in various immune cells such as T cells, B cells and NK cells as well as in cancerous cells. To examine the expression and involvement PI3K isoforms in contributing to FcγR-dependent ADCC by MDMs, we used different inhibitors to specifically target each PI3K isoform at a time to investigate the effect on ADCC responses by MDMs. Examination of PI3K expression showed that PI3Kα, β, and δ are expressed in MDM whereas PI3Kγ is below the limit of detection. We also reported that the PI3Kδ-selective inhibitor, idelalisib and the pan PI3K inhibitor BKM120 (Buparlisib) were able to inhibit ADCC in response to the CD20-targeting therapeutic antibody, obinutuzumab. Similarly, both buparlisib and idelalisib were able to inhibit AKT phosphorylation at concentrations that also inhibited ADCC.
This is the first report to show that PI3Kd is involved in FcgR signalling in MDMs from CLL patients or in MDMs from any tumour type. Based on these findings we conclude that PI3Kd is a critical effector molecule for antitumour responses to therapeutic antibodies in CLL.