Bone Marrow Stromal Cell-Derived IL-8 Upregulates PVR Expression on Multiple Myeloma Cells via NF-kB Transcription Factor

Abstract

Bone marrow stromal cells (BMSCs) strongly contribute to multiple myeloma (MM) progression, promoting the survival and growth of malignant plasma cells (PCs). However, the possible impact of these cells on the immune-mediated recognition of MM cells remains largely unknown. DNAM-1 activating receptor plays a prominent role in NK cell anti-MM response engaging the ligands poliovirus receptor (PVR) and nectin-2 on malignant PCs. Here, we analysed the role of MM patient-derived BMSCs in the regulation of PVR expression. We found that BMSCs enhance PVR surface expression on MM cells and promote their NK cell-mediated recognition. PVR upregulation occurs at transcriptional level and involves NF-kB transcription factor activation by BMSC-derived soluble factors. Indeed, overexpression of a dominant-negative mutant of IKBα blocked PVR upregulation. IL-8 plays a prominent role in these mechanisms since blockade of CXCR1/2 receptors as well as depletion of the cytokine via RNA interference prevents the enhancement of PVR expression by BMSC-derived conditioned medium. Interestingly, IL-8 is associated with stromal microvesicles which are also required for PVR upregulation via CXCR1/CXCR2 signaling activation. Our findings identify BMSCs as regulators of NK cell anti-MM response and contribute to define novel molecular pathways involved in the regulation of PVR expression in cancer cells.

Mesenchymal Stem Cell Immunomodulation: A Novel Intervention Mechanism in Cardiovascular Disease

“…NK cells of peripheral blood mononuclear cell origin from healthy donors were incubated with SKO-007 (J3) cells (Human myeloma cells), some of which were untreated and some of which were incubated with BMSC-CM for 72h, as target cells for degranulation assay. The results showed that CD107a expression was signi cantly elevated in the combined BMSC incubation group, indicating enhanced degranulation of NK cells, and the same results were also observed in patient-derived NK cells against SKO-007 (J3) cells or autologous CD138+ plasma cells treated with BMSC-CM (79). Bone marrow MSCs also modulate the immune activity of hepatic NK cells, and Con A (Concanavalin A) was injected into C57 to model Con A liver injury.…”

Recent Advances on the Pathobiology and Treatment of Multiple Myeloma

“…In particular, the complex interaction with bone marrow stromal cells (BMSCs) strongly supports the survival, proliferation and migration of malignant PCs and promotes osteoclastogenesis and angiogenesis. Mekhloufi et al disclosed a previously unknown immune regulatory role of BMSCs, capable of tuning MM PCs-NK cells cross-talk; in fact, IL-8 secretion by BMSCs triggered an NF-κB dependent expression of PVR ligands on MM PCs, in turn promoting DNAM-1 receptors' recognition and NK cell degranulation [1].…”

Targeting NK Cell Inhibitory Receptors for Precision Multiple Myeloma Immunotherapy

“…PVR is also a ligand recognized by the AR DNAM-1 that is expressed on NK cells. DNAM-1 has been shown to play a prominent role in NK cell-mediated anti-MM response ( 191 ). While TIGIT expression is increased in MM patients, DNAM-1 expression is decreased ( 192 ).…”

“…Furthermore, co-expression of TIGIT with either PD-1 or TIM-3 has been correlated with a dysfunctional phenotype in TILs ( 195 ). Additional studies have shown that PVR expression can be induced by chemotherapy ( 192 ) or by IL-8 signaling through the CXCR1/CXCR2 axis ( 191 ), suggesting that a combination of anti-TIGIT mAbs with chemotherapy may be beneficial when patients’ immune cells have TIGIT expression.…”

“…A better understanding of how NK cell proliferation, function, and expression of receptors or their ligands changes during disease progression as well as in response to specific chemotherapeutics will improve our ability to effectively target NK cells to enhance their anti-tumor response. Specifically, studies have shown that expression of ligands such as PVR, PD-L1 can be enhanced by chemotherapy and/or IFN-γ ( 191 , 192 , 243 ). Similarly, NK cell contact with malignant MM cells was shown to enhance expression of PD-1 and CD94 by a process called trogocytosis ( 67 , 214 ) and LAG-3 due to the exposure to the IFN-α ( 239 ).…”