Frontiers in Immunology (Mar 2024)
Targeting CD73 with flavonoids inhibits cancer stem cells and increases lymphocyte infiltration in a triple-negative breast cancer mouse model
- Karan Mediratta,
- Karan Mediratta,
- Karan Mediratta,
- Karan Mediratta,
- Sara El-Sahli,
- Sara El-Sahli,
- Sara El-Sahli,
- Sara El-Sahli,
- Marie Marotel,
- Marie Marotel,
- Muhammad Z. Awan,
- Muhammad Z. Awan,
- Muhammad Z. Awan,
- Muhammad Z. Awan,
- Melanie Kirkby,
- Melanie Kirkby,
- Melanie Kirkby,
- Melanie Kirkby,
- Ammar Salkini,
- Ammar Salkini,
- Ammar Salkini,
- Ammar Salkini,
- Reem Kurdieh,
- Reem Kurdieh,
- Salman Abdisalam,
- Salman Abdisalam,
- Salman Abdisalam,
- Salman Abdisalam,
- Amit Shrestha,
- Amit Shrestha,
- Amit Shrestha,
- Amit Shrestha,
- Chiara Di Censo,
- Chiara Di Censo,
- Andrew Sulaiman,
- Andrew Sulaiman,
- Andrew Sulaiman,
- Andrew Sulaiman,
- Andrew Sulaiman,
- Sarah McGarry,
- Sarah McGarry,
- Sarah McGarry,
- Sarah McGarry,
- Jessie R. Lavoie,
- Jessie R. Lavoie,
- Zhen Liu,
- Seung-Hwan Lee,
- Seung-Hwan Lee,
- Xuguang Li,
- Xuguang Li,
- Giuseppe Sciumè,
- Giuseppe Sciumè,
- Vanessa M. D’Costa,
- Vanessa M. D’Costa,
- Michele Ardolino,
- Michele Ardolino,
- Michele Ardolino,
- Lisheng Wang,
- Lisheng Wang,
- Lisheng Wang,
- Lisheng Wang,
- Lisheng Wang
Affiliations
- Karan Mediratta
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Karan Mediratta
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Karan Mediratta
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Karan Mediratta
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Sara El-Sahli
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Sara El-Sahli
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Sara El-Sahli
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Sara El-Sahli
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Marie Marotel
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Marie Marotel
- Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Muhammad Z. Awan
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Muhammad Z. Awan
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Muhammad Z. Awan
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Muhammad Z. Awan
- Department of Biotechnology, University of Azad Jammu and Kashmir, Muzaffarabad, Pakistan
- Melanie Kirkby
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Melanie Kirkby
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Melanie Kirkby
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Melanie Kirkby
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Ammar Salkini
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Ammar Salkini
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Ammar Salkini
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Ammar Salkini
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Reem Kurdieh
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Reem Kurdieh
- Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Salman Abdisalam
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Salman Abdisalam
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Salman Abdisalam
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Salman Abdisalam
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Amit Shrestha
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Amit Shrestha
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Amit Shrestha
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Amit Shrestha
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Chiara Di Censo
- Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Chiara Di Censo
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Andrew Sulaiman
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Andrew Sulaiman
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Andrew Sulaiman
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Andrew Sulaiman
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Andrew Sulaiman
- Department of Pathology, John Hopkins University School of Medicine, Baltimore, MD, United States
- Sarah McGarry
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Sarah McGarry
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Sarah McGarry
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Sarah McGarry
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Jessie R. Lavoie
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Jessie R. Lavoie
- Centre for Oncology, Radiopharmaceuticals and Research, Biologic and Radiopharmaceutical Drugs Directorate, Health Products and Food Branch, Health Canada, Ottawa, ON, Canada
- Zhen Liu
- 0State Key Laboratory of Analytical Chemistry for Life Science, School of Chemistry and Chemical Engineering, Nanjing University, Nanjing, China
- Seung-Hwan Lee
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Seung-Hwan Lee
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Xuguang Li
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Xuguang Li
- 1Centre for Biologics Evaluation, Biologics and Genetic Therapies Directorate, Health Canada, Sir Frederick G. Banting Research Centre, Ottawa, ON, Canada
- Giuseppe Sciumè
- Department of Molecular Medicine, Sapienza University of Rome, Rome, Italy
- Giuseppe Sciumè
- 2Instituto Pasteur Italia – Fondazione Cenci Bolognetti, Roma, Italy
- Vanessa M. D’Costa
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Vanessa M. D’Costa
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Michele Ardolino
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Michele Ardolino
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Michele Ardolino
- Ottawa Hospital Research Institute, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Lisheng Wang
- Department of Biochemistry, Microbiology and Immunology, Faculty of Medicine, University of Ottawa, Ottawa, ON, Canada
- Lisheng Wang
- Ottawa Institute of Systems Biology, University of Ottawa, Ottawa, ON, Canada
- Lisheng Wang
- The Centre for Infection, Immunity, and Inflammation (CI3), University of Ottawa, Ottawa, ON, Canada
- Lisheng Wang
- China-Canada Center of Research for Digestive Diseases (ccCRDD), Shanghai University of Traditional Chinese Medicine-University of Ottawa, Ottawa, ON, Canada
- Lisheng Wang
- 3Ottawa Hospital Research Institute, Ottawa, ON, Canada
- DOI
- https://doi.org/10.3389/fimmu.2024.1366197
- Journal volume & issue
-
Vol. 15
Abstract
IntroductionChemotherapy remains the mainstay treatment for triple-negative breast cancer (TNBC) due to the lack of specific targets. Given a modest response of immune checkpoint inhibitors in TNBC patients, improving immunotherapy is an urgent and crucial task in this field. CD73 has emerged as a novel immunotherapeutic target, given its elevated expression on tumor, stromal, and specific immune cells, and its established role in inhibiting anti-cancer immunity. CD73-generated adenosine suppresses immunity by attenuating tumor-infiltrating T- and NK-cell activation, while amplifying regulatory T cell activation. Chemotherapy often leads to increased CD73 expression and activity, further suppressing anti-tumor immunity. While debulking the tumor mass, chemotherapy also enriches heterogenous cancer stem cells (CSC), potentially leading to tumor relapse. Therefore, drugs targeting both CD73, and CSCs hold promise for enhancing chemotherapy efficacy, overcoming treatment resistance, and improving clinical outcomes. However, safe and effective inhibitors of CD73 have not been developed as of now.MethodsWe used in silico docking to screen compounds that may be repurposed for inhibiting CD73. The efficacy of these compounds was investigated through flow cytometry, RT-qPCR, CD73 activity, cell viability, tumorsphere formation, and other in vitro functional assays. For assessment of clinical translatability, TNBC patient-derived xenograft organotypic cultures were utilized. We also employed the ovalbumin-expressing AT3 TNBC mouse model to evaluate tumor-specific lymphocyte responses.ResultsWe identified quercetin and luteolin, currently used as over-the-counter supplements, to have high in silico complementarity with CD73. When quercetin and luteolin were combined with the chemotherapeutic paclitaxel in a triple-drug regimen, we found an effective downregulation in paclitaxel-enhanced CD73 and CSC-promoting pathways YAP and Wnt. We found that CD73 expression was required for the maintenance of CD44highCD24low CSCs, and co-targeting CD73, YAP, and Wnt effectively suppressed the growth of human TNBC cell lines and patient-derived xenograft organotypic cultures. Furthermore, triple-drug combination inhibited paclitaxel-enriched CSCs and simultaneously improved lymphocyte infiltration in syngeneic TNBC mouse tumors.DiscussionConclusively, our findings elucidate the significance of CSCs in impairing anti-tumor immunity. The high efficacy of our triple-drug regimen in clinically relevant platforms not only underscores the importance for further mechanistic investigations but also paves the way for potential development of new, safe, and cost-effective therapeutic strategies for TNBC.
Keywords
- triple-negative breast cancer
- cancer immunotherapy
- CD73
- cancer stem cells
- chemotherapy
- drug repurposing
