Poster Presentation 30th Lorne Cancer Conference 2018

FcγR-mediated responses to therapeutic antibodies by Nurse Like cells are PI3Kδ-dependent in CLL patients (#135)

Yu-Chen Enya Chen 1 , Melinda Burgess 1 , Antje Blumenthal 1 , Sally Mapp 2 , Peter Mollee 2 , Devinder Gill 2 , Nicholas Saunders 1
  1. School of Medicine, University of Queensland, Woolloongabba, QLD, Australia
  2. PA Hospital, Woolloongabba, QLD, Australia

Antibody therapies for treating chronic lymphocytic leukaemia (CLL) remain to be a challenge for many CLL patients who are insensitive to the antibody treatment. High percentage of CLL patients that are resistant to the current combination therapy of chemotherapeutics and immune-therapeutics has always been a major issue. To resolve the issue, understanding the mechanisms driving disease progression and treatment resistance is key to improving patient outcomes. Many studies including our own laboratory have shown the resistance to therapeutic antibodies against CLL is due to the survival signals from the monocyte derived macrophages (MDMs), and also the acquired resistance of MDMs to participate in FcγR-dependent antitumour responses. However, the FcγR-dependent signalling pathway in macrophages has not been well known. Our recently published data suggested that SYK and following by BTK are involved in downstream of FcγR-dependent signalling pathway (referred to as ITAM; Oncogene, 36(17):2366-2376, 2017; BBA Rev on Cancer, 1868:176-182, 2017). This raises an interest to 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 of ADCC responses from 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 PI3Kδ is involved in FcγR signalling in MDMs from CLL patients or in MDMs from any tumour type. Based on these findings we conclude that PI3Kδ is a critical effector molecule for antitumour responses to therapeutic antibodies in CLL.

  1. M Burgess, S Mapp, R Mazzieri, C Cheung, L Chambers, S R Mattarollo, P Mollee, D Gill & N A Saunders. Increased FcγRIIB dominance contributes to the emergence of resistance to therapeutic antibodies in chronic lymphocytic leukaemia patients. Oncogene, Vol. 36, 2366–2376, 2017. doi:10.1038/onc.2016.387
  2. Y.C.E. Chen, S. Mapp, A. Blumenthal, M.L. Burgess, R. Mazzieri, S.R. Mattarollo, P. Mollee, D. Gilla, N.A. Saunders. The duality of macrophage function in chronic lymphocytic leukaemia. Biochim Biophys Acta in Cancer 1868; 176-182, Review. 2017