American Association for Cancer Research

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Supplementary Table S1 from Bortezomib Induces Anti–Multiple Myeloma Immune Response Mediated by cGAS/STING Pathway Activation

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journal contribution
posted on 2023-04-04, 01:04 authored by Annamaria Gulla, Eugenio Morelli, Mehmet K. Samur, Cirino Botta, Teru Hideshima, Giada Bianchi, Mariateresa Fulciniti, Stefano Malvestiti, Rao H. Prabhala, Srikanth Talluri, Kenneth Wen, Yu-Tzu Tai, Paul G. Richardson, Dharminder Chauhan, Tomasz Sewastianik, Ruben D. Carrasco, Nikhil C. Munshi, Kenneth C. Anderson

Supp. table S1 shows immune genes regulated after treatment with bortezomib in vivo.




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The proteasome inhibitor bortezomib induces apoptosis in multiple myeloma cells and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine multiple myeloma models, we here show that bortezomib also triggers immunogenic cell death (ICD), characterized by exposure of calreticulin on dying multiple myeloma cells, phagocytosis of tumor cells by dendritic cells, and induction of multiple myeloma–specific immunity. We identify a bortezomib-triggered specific ICD gene signature associated with better outcome in two independent cohorts of patients with multiple myeloma. Importantly, bortezomib stimulates multiple myeloma cell immunogenicity via activation of the cGAS/STING pathway and production of type I IFNs, and STING agonists significantly potentiate bortezomib-induced ICD. Our study therefore delineates mechanisms whereby bortezomib exerts immunotherapeutic activity and provides the framework for clinical trials of STING agonists with bortezomib to induce potent tumor-specific immunity and improve patient outcome in multiple myeloma. Our study demonstrates that cGAS/STING-dependent immunostimulatory activity mediates bortezomib anti-myeloma activity in experimental models and associates with clinical response to bortezomib in patients with multiple myeloma. These findings provide the rationale for clinical evaluation of STING agonists to further potentiate anti–multiple myeloma immune response.See related commentary by Zitvogel and Kroemer, p. 405.This article is highlighted in the In This Issue feature, p. 403