Bortezomib induces anti-multiple myeloma immune response mediated by cGAS/STING pathway activation

Proteasome inhibitor bortezomib (BTZ) induces apoptosis in myeloma (MM) cells, and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine MM models, we here show that BTZ also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin (CALR) on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a BTZ-triggered specific ICD-gene signature which confers improved outcome in two independent MM patient cohorts. Importantly, BTZ stimulates MM cells immunogenicity via activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate BTZ-induced ICD. Our studies therefore delineate mechanisms whereby BTZ exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with BTZ to induce potent tumor-specific immunity and improve patient outcome in MM. For in vitro study we have triplicates for AMO1 cell line wild type (WT), STING patwhway knockout (KO), WT treated with bortezomib (WT+BTZ) and STING KO treated with BTZ. For in vivo study we have triplicates for 5TGM1 tumors that grew in in C57BL/KaLwRijHsd mice and specifically: 5TGM1 WT, 5TGM1 WT treated with BTZ, 5TGM1 CALR KO, 5TGM1 CALR KO treated with BTZ.