Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer-Reference-Cited by-同舟云学术

Senescence induction dictates response to chemo- and immunotherapy in preclinical models of ovarian cancer

Published:2022-01-26 Issue:5 Volume:119 Page:
ISSN:0027-8424
Container-title:Proceedings of the National Academy of Sciences
language:en
Short-container-title:Proc. Natl. Acad. Sci. U.S.A.

Author:

Paffenholz Stella V.¹²,Salvagno Camilla³⁴,Ho Yu-Jui¹,Limjoco Matthew¹,Baslan Timour¹,Tian Sha¹,Kulick Amanda⁵,de Stanchina Elisa⁵,Wilkinson John E.⁶,Barriga Francisco M.¹,Zamarin Dmitriy⁷,Cubillos-Ruiz Juan R.³⁴⁸,Leibold Josef¹⁹¹⁰,Lowe Scott W.¹¹¹^ORCID

Affiliation:

1. Cancer Biology and Genetics Program, Sloan Kettering Institute, Memorial Sloan Kettering Cancer Center, New York, NY 10065

2. Louis V. Gerstner Jr. Graduate School of Biomedical Sciences, Memorial Sloan Kettering Cancer Center, New York, NY 10065

3. Department of Obstetrics and Gynecology, Weill Cornell Medicine, New York, NY 10065

4. Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY 10065

5. Department of Molecular Pharmacology, Memorial Sloan Kettering Cancer Center, New York, NY 10065

6. Department of Pathology, University of Michigan School of Medicine, Ann Arbor, MI 48109

7. Department of Medicine, Gynecologic Medical Oncology Service, Memorial Sloan Kettering Cancer Center, New York, NY 10065

8. Weill Cornell Graduate School of Biomedical Sciences, Cornell University, New York, NY 10065

9. Department of Medical Oncology & Pneumology (Internal Medicine VIII), University Hospital Tuebingen, Tuebingen 72076, Germany

10. DFG Cluster of Excellence 2180 “Image-Guided and Functional Instructed Tumor Therapy” (iFIT), University of Tuebingen, 72076 Tuebingen, Germany

11. Howard Hughes Medical Institute (HHMI), Memorial Sloan Kettering Cancer Center, New York, NY 10065

Abstract

Significance Efforts to understand and find new treatment options for high-grade serous ovarian cancer (HGSOC) have been confounded by a paucity of immune-competent models that accurately reflect the genetics and biology of the disease. Here, we leverage somatic tissue engineering to develop a fast and flexible immune-competent mouse model of HGSOC and reveal mechanistic insights into factors that dictate the response of ovarian tumors to conventional chemotherapy and immune checkpoint blockade. Our results identify a genotype-dependent therapy-induced senescence program that mediates sensitivity and resistance to first line chemotherapy and point to strategies to harness the senescence program to sensitize ovarian tumors to immune checkpoint blockade.

Funder

HHS | NIH | National Cancer Institute

HHS | National Institutes of Health

U.S. Department of Defense

EIF | Stand Up To Cancer

Deutsche Forschungsgemeinschaft

Publisher

Proceedings of the National Academy of Sciences

Subject

Multidisciplinary

Link

https://pnas.org/doi/pdf/10.1073/pnas.2117754119