ABSTRACT
Human bone marrow permanently harbors high numbers of neutrophils, and a tumor-supportive bias of these cells could significantly impact bone marrow-confined malignancies. In individuals with multiple myeloma, the bone marrow is characterized by inflammatory stromal cells with the potential to influence neutrophils. We investigated myeloma-associated alterations in human marrow neutrophils and the impact of stromal inflammation on neutrophil function. Mature neutrophils in myeloma marrow are activated and tumor supportive and transcribe increased levels of IL1B and myeloma cell survival factor TNFSF13B (BAFF). Interactions with inflammatory stromal cells induce neutrophil activation, including BAFF secretion, in a STAT3-dependent manner, and once activated, neutrophils gain the ability to reciprocally induce stromal activation. After first-line myeloid-depleting antimyeloma treatment, human bone marrow retains residual stromal inflammation, and newly formed neutrophils are reactivated. Combined, we identify a neutrophil-stromal cell feed-forward loop driving tumor-supportive inflammation that persists after treatment and warrants novel strategies to target both stromal and immune microenvironments in multiple myeloma.
Subject(s)
B-Cell Activating Factor , Interleukin-1beta , Multiple Myeloma , Neutrophils , Stromal Cells , Tumor Microenvironment , Multiple Myeloma/immunology , Multiple Myeloma/pathology , Humans , Tumor Microenvironment/immunology , Neutrophils/immunology , Neutrophils/metabolism , Stromal Cells/metabolism , Stromal Cells/immunology , B-Cell Activating Factor/metabolism , Interleukin-1beta/metabolism , Neutrophil Activation , STAT3 Transcription Factor/metabolism , Bone Marrow/immunology , Bone Marrow/pathologyABSTRACT
INTRODUCTION: The established method for assessment of mediastinal and hilar lymph nodes is endobronchial ultrasound bronchoscopy (EBUS) with needle aspirations. Previously, we presented an electromagnetic navigation platform for this purpose. There were several issues with the permanent electromagnetic tracking (EMT) sensor attachment on the tip of the experimental EBUS bronchoscope. The purpose was to develop a device for on-site attachment of the EMT sensor. MATERIAL AND METHODS: A clip-on EMT sensor attachment device was 3D-printed in Ultem™ and attached to an EBUS bronchoscope. A specially designed ultrasound probe calibration adapter was developed for on-site and quick probe calibration. Navigation accuracy was studied using a wire cross water phantom and clinical feasibility was tested in a healthy volunteer. RESULTS: The device attached to the EBUS bronchoscope increased its diameter from 6.9 mm to 9.5 mm. Average preclinical navigation accuracy was 3.9 mm after adapter calibration. The maneuvering of the bronchoscope examining a healthy volunteer was adequate without harming the respiratory epithelium, and the device stayed firmly attached. CONCLUSION: Development, calibration and testing of a clip-on EMT sensor attachment device for EBUS bronchoscopy was successfully demonstrated. Acceptable accuracy results were obtained, and the device is ready to be tested in patient studies.
