Epigenetic treatment of multiple myeloma mediates tumor intrinsic and extrinsic immunomodulatory effects

Abstract

Immune evasion is an important driver of disease progression in the plasma cell malignancy multiple myeloma. Recent work highlights the potential of epigenetic modulating agents as tool to enhance anti-tumor immunity. The immune modulating effects of the combination of a DNA methyltransferase inhibitor and a histone deacetylase inhibitor in multiple myeloma is insufficiently characterized. Therefore, we used the murine immunocompetent 5T33MM model to investigate hallmarks of immunogenic cell death as well as alterations in the immune cell constitution in the bone marrow of diseased mice in response to the DNA methyltransferase inhibitor decitabine and the histone deacetylase inhibitor quisinostat. Vaccination of mice with 5T33 cells treated with epigenetic compounds delayed tumor development upon a subsequent tumor challenge. In vitro, epigenetic treatment induced ecto-calreticulin and CD47, as well as a type I interferon response. Moreover, treated 5T33vt cells triggered dendritic cell maturation. The combination of decitabine and quisinostat in vivo resulted in combinatory anti-myeloma effects. In vivo, epigenetic treatment increased tumoral ecto-calreticulin and decreased CD47 and PD-L1 expression, increased dendritic cell maturation and reduced CD11b positive cells. Moreover, epigenetic treatment induced a temporal increase in presence of CD8-positive and CD4-positive T cells with naive and memory-like phenotypes based on CD62L and CD44 expression levels, and reduced expression of exhaustion markers PD-1 and TIM3. In conclusion, a combination of a DNA methyltransferase inhibitor and a histone deacetylase inhibitor increased the immunogenicity of myeloma cells and altered the immune cell constitution in the bone marrow of myeloma-bearing mice.

Trial watch: chemotherapy-induced immunogenic cell death in immuno-oncology

“…12,24,57,113,119,224,237 Ultimately, APCs engulfing TAAs or TSAs and receiving these immunostimulatory cues acquire an extraordinary ability to crosspresent TAA-or TSA-derived epitopes to CD4 + and/or CD8 + T cells in the context of co-stimulation, which enables TAA/TSAtargeting immunity. [239][240][241][242][243][244] In multiple oncological settings, cancer cells capable of undergoing ICD in response to microenvironmental or therapeutic stress are subjected to increased immunological pressure, 245 resulting in the selection of poorly immunogenic tumor variants displaying: (1) reduced antigenicity (due to TAA/TSA loss or defects in MHC Class I exposure); [246][247][248][249][250][251][252][253] (2) genetic or epigenetic annihilation of the intracellular stress pathways that support the emission of ICD-associated DAMPs, cytokines or chemokines; 254 and/or (3) direct genetic or epigenetic silencing of specific DAMPs (e.g. CALR) or type I IFN.…”

Commentary: Immunogenic Cell Death and Immunotherapy of Multiple Myeloma

“…In case bona fide ICD occurs, mice will be protected against a challenge with living tumor cells. We were the first to perform this vaccination assay using the syngeneic immunocompetent 5T33MM model (De Beck et al, 2018). The vaccine consisted of 5T33vt cells treated with bortezomib, melphalan, a DNA methyltransferase inhibitor (decitabine), a histone deacetylase inhibitor (quisinostat) or the combination of decitabine and quisinostat.…”

Lower expression of the RASSF10 gene induces myeloma cell proliferation due to hypermethylation of the gene promoter in multiple myeloma

“…However, use of AZA or decitabine in MM is limited because of induction of DNA damage. Recent research showed that decitabine enhanced the effect of bortezomib in an MM cell line (29). Decitabine, combined with quisinostat, a histone deacetylase inhibitor, showed increased antimyeloma effects and altered immune cell constitution, such as increased dendritic cells and naive T cells, in a mouse myeloma model (30).…”