The mitochondrial protease ClpP is a metabolic vulnerability and an immunogenic trigger against multiple myeloma
Abstract
Abstract Orchestrating key homeostatic functions, mitochondria likely entail cancer vulnerabilities. Moreover, because of their bacterial ancestry, they can release potent immunogenic signals. In this study, we showed that the mitochondrial protease caseinolytic peptidase P (ClpP) is both a cell-intrinsic metabolic vulnerability and an actionable immunogenic trigger in multiple myeloma (MM). We found that ClpP messenger RNA is higher in bone marrow (BM)-purified malignant plasma cells than in normal or premalignant counterparts and that MM lines rank first in ClpP expression among human cancers. Moreover, we demonstrated that human MM cells are highly vulnerable to ClpP inhibition in vitro and in vivo. Surprisingly, MM cell dependence on ClpP was not accounted for by its acknowledged oxidative phosphorylation surveillance activity. Proteomic discovery of proteolytic targets, metabolomics, and metabolic tracing identified a critical control exerted by ClpP on ornithine aminotransferase abundance to sustain cytosolic biosynthesis of polyamines, which are essential for MM cells. Transcriptomics and targeted validation also revealed the activation of a cyclic GMP-AMP synthase (cGAS)–dependent type I interferon (IFN) response in ClpP-silenced MM cells, whose supernatants boosted dendritic cell activation and ability to stimulate IFN-γ production by T cells. In vivo, ClpP silencing reshaped the BM immune environment in immunocompetent mice by significantly expanding IFN-γ–producing CD4+ and CD8+ T cells and CD4+ T memory cells, while containing exhausted CD4+ T cells and myeloid-derived suppressor cells. Thus, ClpP is a newly identified addiction of MM cells whose inhibition not only exerts cell-intrinsic toxicity but also triggers otherwise indolent antitumoral immunity. Our findings yield a novel immunogenic chemotherapeutic framework with potential relevance to myeloma.
Article Details
Authors (23)
Tommaso Perini
1Age Related Diseases Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Paola Zordan
Rossella Del Pizzo
Massimo Resnati
1Age Related Diseases Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Lisa Viviani
1Age Related Diseases Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Davide Stefanoni
2Division of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
Laura Cassina
2Division of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
Ugo Orfanelli
1Age Related Diseases Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Matteo Trudu
1Age Related Diseases Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Laura Oliva
1Age Related Diseases Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Daniel Lacidogna
1Age Related Diseases Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Mehmet K. Samur
Dana-Farber Cancer Institute and Harvard School of Public Health, Boston, Massachusetts, United States
Maria Materozzi
1Age Related Diseases Unit, Division of Genetics and Cell Biology, IRCCS Ospedale San Raffaele, Milan, Italy
Denise Drago
7Proteomics and Metabolomics Facility, Center for Omics Sciences, IRCCS Ospedale San Raffaele, Milan, Italy
Annapaola Andolfo
7Proteomics and Metabolomics Facility, Center for Omics Sciences, IRCCS Ospedale San Raffaele, Milan, Italy
Marco Patrone
Biocrystallography Unit, Division of Immunology, Transplantation, and Infectious Diseases, Istituto Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute
Massimo Degano
Alessandra Boletta
2Division of Genetics and Cell Biology, Istituto di Ricovero e Cura a Carattere Scientifico San Raffaele Scientific Institute, Milan, Italy
Enrico Milan
1Istituto di Ricovero e Cura a Carattere Scientifico Ospedale San Raffaele
Fabio Ciceri
Vita-Salute San Raffaele University, Milan
Nikhil C. Munshi
Matteo Bellone
Simone Cenci