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1930 CREB1 Promotes Immune Escape of Multiple Myeloma Cells By Inducing HLA-E

Program: Oral and Poster Abstracts
Session: 651. Multiple Myeloma and Plasma Cell Dyscrasias: Basic and Translational: Poster I
Hematology Disease Topics & Pathways:
Research, Fundamental Science, apoptosis, Translational Research, Plasma Cell Disorders, Diseases, immune mechanism, Lymphoid Malignancies, Biological Processes, molecular biology, pathogenesis
Saturday, December 9, 2023, 5:30 PM-7:30 PM

Aya Ismael1*, Allen Robinette2*, Kameron Dona1,3*, Ruchi Kudalkar1*, Vincent Manning1*, Joshua Galloway1*, Emanuele Cocucci, MD, PhD4* and Francesca Cottini, MD1

1The Ohio State University, Columbus, OH
2Division of Hematology, The Ohio State University Wexner Medical Center, Columbus, OH
3Penn State University, State College, PA
4College of Pharmacy, The Ohio State University, Columbus, OH

Introduction: Multiple Myeloma (MM) is a disease of clonal plasma cells, which accumulate in the bone marrow (BM) and rely on the support of the microenvironment to survive. Immune escape is a common resistance mechanism employed by tumor cells to avoid cytotoxicity by effector immune cells. HLA-E, a non-classical major histocompatibility complex (MHC) class I molecule, inhibits the function of specific subtypes of Natural Killer (NK) and T cells, leading to tumor immune escape. HLA-E expression correlates with worse progression-free survival in newly diagnosed patients with MM. Therefore, we decided to better elucidate the function and regulation of HLA-E expression in MM.

Results: We observed that HLA-E mRNA expression increases in the transformation from normal plasma cells to MM. Since INF-gamma induces HLA-E in MM cells and CREB1 itself promotes the production of IFN-gamma, we hypothesize that CREB1 could regulate HLA-E expression in MM. We first analyzed RNA-sequencing data from patients with MM in the CoMMpass database: gene set enrichment analysis (GSEA) showed increased expression of several pathways related to interferon signaling in patients with high CREB1 expression. We then specifically looked at differences in HLA-E and we confirmed that patients with high CREB1 expression had statistically significant higher HLA-E levels compared with patients with low CREB1 expression. CHIP-sequencing assays in MM cell lines demonstrated that CREB1 can directly influence HLA-E expression by binding to HLA-E promoter. To further prove these data, we evaluated HLA-E levels in gain-of and loss-of function models of CREB1. We observed an increase of HLA-E levels by overexpression of wild type CREB1 and reduction of HLA-E levels by CREB1 silencing or pharmacological inhibition of CREB1 with 666-15 (CREBi).

We then investigated the relationship between CREB1 and STAT1. Indeed, IFN-gamma signals through the STAT1-JAK pathway. Interestingly, while treatment with IFN-gamma strongly induces HLA-E without affecting CREB1 levels or its function, CREBi + INF-gamma reduces HLA-E, STAT1, and phospho-STAT1 levels. Conversely, immunomodulatory drugs (lenalidomide-LEN and pomalidomide-POM) and HDAC inhibitor, Panobinostat, promote the phosphorylation of STAT1, resulting in the transcription of IFN-target genes, including HLA-E. The increase in HLA-E was then reverted by CREB1 inhibition. Since HLA-E impairs NK cell function, we treated MM cells in the presence of NK cells with CREBi alone or in combination with immunomodulatory drugs (IMiDs). Treatment with CREBi or CREBi + IMiDs potentiated the killing effects of NK cells. Animal studies are ongoing to confirm these data in vivo.

Conclusion: In conclusion, our study defines the role of CREB1 in modulating HLA-E expression; CREB1 inhibition improves NK cell-mediated cytotoxicity in MM, representing a novel strategy to tackle immune escape.

Disclosures: Cottini: The Dedham Group: Consultancy; Techspert Network: Consultancy.

*signifies non-member of ASH