Dying cells can release danger-associated molecular patterns (DAMPs) and trigger an adaptive immune response, a process known as immunogenic cell death (ICD). Induction of ICD depends on the therapy and the capacity of cells to release the necessary DAMPs. Multiple myeloma (MM) is a plasma cell cancer which develops in the bone marrow. MM cells escape from the immune system via the PD1/PDL1 pathway and presence of inhibitory immune cells. Occurrence of ICD in MM cells has not been studied thoroughly. Better understanding of ICD in MM may result in strategies that exploit ICD to improve current therapies. Here, we investigated ICD in the 5T33 immunocompetent murine model for MM in response to chemotherapeutics (melphalan, bortezomib, mitoxanthrone), a DNA methyltransferase inhibitor decitabine and a histone deacetylase inhibitor quisinostat. Decitabine and quisinostat-treated 5T33vt cells and to a lesser extent melphalan and mitoxanthrone-treated cells increased the expression of maturation markers upon co-culture with bone marrow-derived dendritic cells. Vaccination of mice with 5T33vt cells treated with melphalan, mitoxanthrone or the combination of decitabine and quisinostat, delayed tumor progression and resulted in at most 30% tumor free mice indicating sub-optimal induction of ICD. We next investigated molecular hallmarks of ICD. Regardless of the treatment, an increased expression of calreticulin in 7AAD negative 5T33vt cells was observed which coincided with annexinV positivity. Moreover, the expression of the “don’t eat me” signal, CD47, was increased upon treatment. No increase in HMGB1 release above control conditions was observed. Melphalan, bortezomib, decitabine and quisinostat induced the expression of Ifnb and interferon stimulated genes (Mx1, Oasl2, Ifi27, Cxcl10). To conclude, dying murine myeloma cells have a limited ICD-inducing capacity, potentially due to the presence of CD47, absence of HMGB1 and co-incidence of calreticulin and phospatidylserine. These results warrant further validation in human MM cells.
|Publication status||Unpublished - 2018|
|Event||EACR: A matter of life and death - De Rode Hoed, Amsterdam, Netherlands|
Duration: 1 Feb 2018 → 3 Feb 2018
|Conference||EACR: A matter of life and death|
|Period||1/02/18 → 3/02/18|