Using multiple myeloma (MM) models, Gulla et al. showed that the proteasome inhibitor bortezomib (BTZ) induced immunogenic cell death marked by calreticulin surface exposure on dying MM cells, which allowed their phagocytosis by DCs, stimulating MM-specific primary and recall T cell responses. BTZ treatment of MM cells upregulated 90 immune-related genes enriched with IFN-stimulated genes inducible by the cGAS/STING pathway. BTZ-induced antitumor activity was activated by STING agonists and inhibited by blocking type I IFNs. The gene signature strongly positively correlated with the clinical outcome of two cohorts of patients with MM treated with BTZ.
Contributed by Paula Hochman
ABSTRACT: Proteasome inhibitor bortezomib induces apoptosis in multiple 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 bortezomib also triggers immunogenic cell death (ICD) characterized by exposure of calreticulin on dying MM cells, phagocytosis of tumor cells by dendritic cells, and induction of MM specific immunity. We identify a bortezomib-triggered specific ICD-gene signature associated with better outcome in two independent MM patient cohorts. Importantly, bortezomib stimulates MM cells immunogenicity via activation of cGAS/STING pathway and production of type-I interferons; and STING agonists significantly potentiate bortezomib-induced ICD. Our studies therefore delineate mechanisms whereby bortezomib exerts immunotherapeutic activity, and provide the framework for clinical trials of STING agonists with bortezomib to induce potent tumor-specific immunity and improve patient outcome in MM.