The immunogenic effects of chemotherapy and epigenetic modulating agents in the 5T33 murine model for multiple myeloma.

Research output: Unpublished contribution to conferencePoster

Abstract

Immunogenic cell death (ICD) is the process where dying cells release danger-associated molecular patterns (DAMPs) and trigger an adaptive immune response. Treatment of cancer cells with chemotherapeutics can result in ICD and the development of anti-tumor CD8+ T cells but not all cancer types can undergo bona fide ICD. Epigenetic modulating agents (EMAs) including the DNA methyltransferase inhibitors (DNMTi) and histone deacetylase inhibitors (HDACi) boost anti-tumoral immune responses by induction of antigen expression, reversal of the immune-suppressive microenvironment and viral mimicry. Multiple myeloma (MM) is a plasma cell cancer which develops in the bone marrow. MM progression is enhanced by escape from the immune system via the PD1/PDL1 pathway and inhibitory immune cells. Whether MM cells undergo ICD has not been studied thoroughly. Better understanding of ICD in MM is useful as defects in ICD may compromise the efficacy of current therapies. Here, we investigated ICD in the immunocompetent murine 5T33 model for MM in response to chemotherapeutics (melphalan, bortezomib, mitoxanthrone), the DNMTi decitabine and the HDACi quisinostat. Treatment of 5T33vt cells with chemotherapeutics and EMAs induced calreticulin exposure which correlated with annexinV positivity. No increase in HMGB1 release above control conditions was observed. Both chemotherapeutics and EMAs induced the expression of Ifnb and interferon stimulated genes (Mx1, Oasl2, Ifi27, Cxcl10). In contrast to chemotherapy treated 5T33vt cells, EMA-treated 5T33vt cells increased the expression of CD40, MHCI, MHCII, CD80 and CD86 upon co-culture with bone marrow-derived dendritic cells (DCs). Mice vaccinated with 5T33vt cells treated with melphalan, mitoxanthrone or a combination of decitabine and quisinostat showed a significant delay in progression but no full protection against subcutaneous plasmacytome development. In conclusion, 5T33vt cells display features of ICD is response to chemotherapy and EMAs. However, no complete protection against tumor formation was induced indicating sub-optimal induction of anti-MM immune responses.
Original languageEnglish
Publication statusPublished - 2017
EventEACR: Defence is the best attack: Immuno-oncology breakthroughs - Passeig de Gracia, 92, Barcelona, Spain
Duration: 9 Oct 201711 Oct 2017
https://www.eacr.org/conference/immunooncology17

Conference

ConferenceEACR: Defence is the best attack: Immuno-oncology breakthroughs
CountrySpain
CityBarcelona
Period9/10/1711/10/17
Internet address

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