Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer.
cancer immunotherapy
mouse models
ovarian cancer
senescence
Journal
Proceedings of the National Academy of Sciences of the United States of America
ISSN: 1091-6490
Titre abrégé: Proc Natl Acad Sci U S A
Pays: United States
ID NLM: 7505876
Informations de publication
Date de publication:
01 02 2022
01 02 2022
Historique:
accepted:
22
11
2021
entrez:
27
1
2022
pubmed:
28
1
2022
medline:
25
2
2022
Statut:
ppublish
Résumé
High-grade serous ovarian carcinoma (HGSOC) is a cancer with dismal prognosis due to the limited effectiveness of existing chemo- and immunotherapies. To elucidate mechanisms mediating sensitivity or resistance to these therapies, we developed a fast and flexible autochthonous mouse model based on somatic introduction of HGSOC-associated genetic alterations into the ovary of immunocompetent mice using tissue electroporation. Tumors arising in these mice recapitulate the metastatic patterns and histological, molecular, and treatment response features of the human disease. By leveraging these models, we show that the ability to undergo senescence underlies the clinically observed increase in sensitivity of homologous recombination (HR)-deficient HGSOC tumors to platinum-based chemotherapy. Further, cGas/STING-mediated activation of a restricted senescence-associated secretory phenotype (SASP) was sufficient to induce immune infiltration and sensitize HR-deficient tumors to immune checkpoint blockade. In sum, our study identifies senescence propensity as a predictor of therapy response and defines a limited SASP profile that appears sufficient to confer added vulnerability to concurrent immunotherapy and, more broadly, provides a blueprint for the implementation of electroporation-based mouse models to reveal mechanisms of oncogenesis and therapy response in HGSOC.
Identifiants
pubmed: 35082152
pii: 2117754119
doi: 10.1073/pnas.2117754119
pmc: PMC8812522
pii:
doi:
Substances chimiques
Antineoplastic Agents
0
Immune Checkpoint Inhibitors
0
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Subventions
Organisme : NCI NIH HHS
ID : P30 CA008748
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA233944
Pays : United States
Organisme : NINDS NIH HHS
ID : R01 NS114653
Pays : United States
Organisme : NCI NIH HHS
ID : R21 CA248106
Pays : United States
Informations de copyright
Copyright © 2022 the Author(s). Published by PNAS.
Déclaration de conflit d'intérêts
Competing interest statement: T.B. holds equity in Roche, Genenetech, and Novartis and has received consulting fees from Illumina, Oxford Nanopore, and Pacific Biosciences. D.Z. reports research funding to Memorial Sloan Kettering Cancer Center from AstraZeneca, Genentech, and Plexxikon; personal fees from Synlogic Therapeutics, Hookipa Biotech, Agenus, Synthekine, Memgen, Mana Therapeutics, Tessa Therapeutics, and Xencor; stock options from Accurius, Calidi Biotherapeutics, and ImmunOs, and is an inventor on a patent concerning the use of Newcastle disease virus as a cancer therapeutic, licensed to Merck. J.R.C.-R. is a member of the scientific advisory board of NextRNA Therapeutics, Inc. S.W.L. is a founder and member of the scientific advisory board of Blueprint Medicines, Mirimus, Inc., ORIC Pharmaceuticals, Geras Bio, and Faeth Therapeutics, and is on the scientific advisory board of PMV Pharmaceuticals. None of these affiliations represent a conflict of interest with respect to the design or execution of this study or interpretation of data presented in this report.
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