Abstract 4837: NSD2 modulates immune surveillance in multiple myeloma

Abstract Background: The histone methyltransferase NSD2 is overexpressed in 15% of multiple myeloma (MM) patients due to the translocation (4;14). NSD2 overexpression disrupts chromatin methylation promoting oncogenic gene expression. Despite advancements in MM treatments, the t(4;14) translocation remains a poor prognostic marker. Interestingly, NSD2 disruption in t(4;14) MM cell lines does not affect cellular fitness in vitro, suggesting its oncogenic effects might involve mechanisms beyond intrinsic cancer cell survival. Emerging evidence indicates a role of NSD2 in tumor immune response. In vivo CRISPR screens showed that NSD2 is selectively crucial when tumor cells are engrafted into immunocompetent mice, suggesting that NSD2 contributes to immune evasion. Targeting NSD2-mediated immune suppression shows potential therapeutic benefits in t(4;14) MM. Aim: To investigate the role of NSD2 in modulating immune surveillance in MM. Methods: Multi-omics analyses were performed on isogenic t(4;14) MM cell lines with varying NSD2 expression. These analyses were supported by targeted assays, including flow cytometry and multiplex immunoassays. We utilized both immunocompetent and immunodeficient MOPC315.BM myeloma mouse models to study NSD2’s role in immune modulation in vivo. Results: RNA-seq analysis revealed that NSD2 regulates several immune-related pathways, with a particularly strong suppression of MHC-II gene expression in NSD2-overexpressing cells. Unbiased proteomics confirmed reduced MHC-II protein levels in these cells. Flow cytometry showed that disrupting NSD2 in t(4;14) MM cells increases MHC-II expression, an effect reversed by conditioned media from NSD2-high cells. This suggests that NSD2 promotes secretion of factors that suppress MHC-II expression, reducing antigen presentation and ultimately the immune response. NSD2 inhibitor treatment increased MHC-II expression, indicating potential for immunotherapy. Cytokine and chemokine profiling revealed that NSD2 overexpression alters the secretion of CCL2, CXCL9, MCP-1, IL-16, and IL-10, with implications for immune modulation. Metabolomics showed that NSD2-high cells accumulate the immunosuppressive metabolite spermidine. Proteomics further revealed marked reduction of adenosine deaminases ADA1 and ADA2 by NSD2, suggesting an accumulation of the immunosuppressive metabolite adenosine in the tumor microenvironment. Conclusion: NSD2 overexpression in MM suppresses immune surveillance potentially contributing to the aggressiveness of t(4;14) myelomas. These findings highlight the potential of NSD2 as a therapeutic target to enhance immunotherapy in MM. Future directions: The effect NSD2 on MM eradication by immune cells will be investigated by immune cell killing assays. The immunocompetent MOPC315.BM MM model will be used to evaluate how NSD2 regulates immune cell composition. Citation Format: Amin Sobh, Daphne Dupere-Richer, Emilie Bonilla, Guya Avshara, Karthik Vasan, Monica Clerio, Richard Bennett, Navdeep S. Chandel, Jonathan D. Licht. NSD2 modulates immune surveillance in multiple myeloma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 1 (Regular Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_1):Abstract nr 4837.