GAS6/TAM signaling pathway controls MICA expression in multiple myeloma cells

• Authors: Andrea Kosta, Sapienza University of Rome; Abdelilah Mekhloufi, Emory University; Lorenzo Lucantonio, Sapienza University of Rome; Alessandra Zingoni, Sapienza University of Rome; Alessandra Soriani, Sapienza University of Rome; Marco Cippitelli, Sapienza University of Rome; Angela Gismondi, Sapienza University of Rome; Francesca Fazio, Sapienza University of Rome; Maria Teresa Petrucci, Sapienza University of Rome; Angela Santoni, Sapienza University of Rome; Helena Stabile, Sapienza University of Rome; Cinzia Fionda, Sapienza University of Rome
• Journal Title: Frontiers in Immunology
• Volume: Volume 13
• Publisher: Frontiers Media | 2022-07-28
• Type of Work: Article | Final Publisher PDF
• Publisher DOI: http://doi.org/10.3389/fimmu.2022.942640
• Subjects: Engineering, Biomedical; Health Sciences, Oncology
• Keywords: GAS6; AXL; MERTK; MICA; NKG2D ligand; multiple myeloma; natural killer cells; bone marrow stromal cells

Abstract

NKG2D ligands play a relevant role in Natural Killer (NK) cell -mediated immune surveillance of multiple myeloma (MM). Different levels of regulation control the expression of these molecules at cell surface. A number of oncogenic proteins and miRNAs act as negative regulators of NKG2D ligand transcription and translation, but the molecular mechanisms sustaining their basal expression in MM cells remain poorly understood. Here, we evaluated the role of the growth arrest specific 6 (GAS6)/TAM signaling pathway in the regulation of NKG2D ligand expression and MM recognition by NK cells. Our data showed that GAS6 as well as MERTK and AXL depletion in MM cells results in MICA downregulation and inhibition of NKG2D-mediated NK cell degranulation. Noteworthy, GAS6 derived from bone marrow stromal cells (BMSCs) also increases MICA expression at both protein and mRNA level in human MM cell lines and in primary malignant plasma cells. NF-kB activation is required for these regulatory mechanisms since deletion of a site responsive for this transcription factor compromises the induction of mica promoter by BMSCs. Accordingly, knockdown of GAS6 reduces the capability of BMSCs to activate NF-kB pathway as well as to enhance MICA expression in MM cells. Taken together, these results shed light on molecular mechanism underlying NKG2D ligand regulation and identify GAS6 protein as a novel autocrine and paracrine regulator of basal expression of MICA in human MM cells.