Idelalisib impairs TREM-1 mediated neutrophil inflammatory responses

Astrid Alflen,Markus P. Radsak,Daniel Teschner,Nicole Stadler,Pamela Aranda Lopez,Matthias Theobald,Georg Heß

doi:10.1038/s41598-018-23808-2

Abstract

Triggering receptor expressed on myeloid cells (TREM)-1 on polymorphonuclear neutrophils (PMN) regulates innate immune activation in infectious and non-infectious conditions. TREM-1 ligation activates phosphatidyl-inositol 3 kinase (PI3K) triggering all neutrophil effector functions. As idelalisib is a PI3K inhibitor in clinical use for the treatment of non-Hodgkin lymphomas, we asked whether this inhibitor affects PMN functionalities. We analyzed PMNs from healthy donors or lymphoma patients for oxidative burst, phagocytosis, activation markers and IL-8 release upon TREM-1 or TLR ligation ex vivo. In addition, we performed western blot analyses to characterize the signaling events inhibited by idelalisib and other PI3K inhibitors. Upon TREM-1 ligation, the oxidative burst, degranulation, L-selectin shedding and cytokine release were all strongly reduced in the presence of idelalisib along impaired phosphorylation of P38, AKT and ERK by western blot analyses. In line with this, PMNs from patients receiving idelalisib also displayed an impaired TREM-1 mediated PMN activation ex vivo. In conclusion, PI3K inhibitors might cause a neutropenia-like susceptibility to infections in patients by leading to impaired PMN functionality. This should be considered when evaluating patients for infections treated with such inhibitors in daily clinical routine.

Highlights

We demonstrate that idelalisib preferentially abrogated the Triggering receptor expressed on myeloid cells (TREM)-1 mediated neutrophil activation of the oxidative burst, degranulation, CD62L shedding and interleukine-8 (IL-8) release and suppresses TREM-1 associated signaling events downstream of phosphatidyl-inositol 3 kinase (PI3K), while only the TLR4 mediated oxidative burst was impaired
To assess whether idelalisib affects TREM-1 and TLR4 mediated neutrophil activation, we stimulated neutrophils from healthy volunteer donors with TREM-1 specific mAb or LPS in the absence or presence of idelalisib 1 μg/ml
Idelalisib abrogates TREM-1 mediated neutrophil activation in terms of the oxidative burst, degranulation and IL-8 release, while TLR4 mediated neutrophil activation is only affected concerning the oxidative burst, suggesting that this drug may be useful in modulating neutrophil functionality in a targeted way

Summary

Introduction

PI3K inhibitors might cause a neutropenia-like susceptibility to infections in patients by leading to impaired PMN functionality. Investigations especially concerning the combination therapy with monoclonal antibodies revealed that idelalisib affects lymphatic cells, and impairs innate immune functions, e.g. natural killer (NK) cell degranulation, neutrophil activation and phagocytosis by macrophages[4]. This suggests that idelalisib may impair innate immune responses in patients under treatment with this drug, possibly further aggravating the well-known secondary immunodeficiencies in CLL or FL patients

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Results

Conclusion