Activation of FCYR-dependent responses to therapeutic antibodies by nurse like cells requires PI3KS

Antibody therapies for treating chronic lymphocytic leukemia (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 have 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 FcγRdependent anti-tumor responses. However, the FcγR-dependent signaling pathway in macrophages has not been well studied. Our recently published data suggested that SYK and BTK are involved downstream of FcγR-dependent signaling pathway. 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 observe the expression and involvement PI3K isoforms in contributing to FcγR-structured ADCC by means of MDMs, we used special inhibitors to in particular target each PI3K isoform at a time to analyze the impact on ADCC responses via MDMs. Examination of PI3K expression confirmed that PI3Kα, β and δ are expressed in MDM while PI3Kγ is underneath the limit of detection. We also suggested that the PI3Kδ-selective inhibitor, idelalisib and the pan PI3K inhibitor BKM120 (Buparlisib) were able to inhibit ADCC in reaction to the CD20-targeting healing antibody, obinutuzumab. Similarly, each buparlisib and idelalisib were able to inhibit AKT phosphorylation at concentrations that still inhibited ADCC. This is the first report to expose that PI3Kδ is worried in FcγR signaling in MDMs from CLL sufferers or in MDMs from any tumor type. Based on those findings we conclude that PI3Kδ is a important effector molecule for anti-tumor responses to healing antibodies in CLL.

Author(s): Yu-Chen Enya Chen, Burgess M, Blumenthal A, Mapp S, Mollee P, GillD and Saunders N A

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