Frontiers in Immunology (Mar 2023)
Fatty acid transport protein inhibition sensitizes breast and ovarian cancers to oncolytic virus therapy via lipid modulation of the tumor microenvironment
- Abera Surendran,
- Abera Surendran,
- Monire Jamalkhah,
- Monire Jamalkhah,
- Joanna Poutou,
- Rayanna Birtch,
- Rayanna Birtch,
- Christine Lawson,
- Jaahnavi Dave,
- Jaahnavi Dave,
- Mathieu J. F. Crupi,
- Mathieu J. F. Crupi,
- Justin Mayer,
- Victoria Taylor,
- Julia Petryk,
- Christiano Tanese de Souza,
- Neil Moodie,
- Jacob Lecompte Billingsley,
- Bradley Austin,
- Nicole Cormack,
- Natalie Blamey,
- Reza Rezaei,
- Reza Rezaei,
- Curtis W. McCloskey,
- Curtis W. McCloskey,
- Emily E. F. Fekete,
- Emily E. F. Fekete,
- Harsimrat K. Birdi,
- Harsimrat K. Birdi,
- Serge Neault,
- Serge Neault,
- Taylor R. Jamieson,
- Taylor R. Jamieson,
- Brenna Wylie,
- Sarah Tucker,
- Taha Azad,
- Taha Azad,
- Barbara Vanderhyden,
- Barbara Vanderhyden,
- Lee-Hwa Tai,
- John C. Bell,
- John C. Bell,
- Carolina S. Ilkow,
- Carolina S. Ilkow
Affiliations
- Abera Surendran
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Abera Surendran
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Monire Jamalkhah
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Monire Jamalkhah
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Joanna Poutou
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Rayanna Birtch
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Rayanna Birtch
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Christine Lawson
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Jaahnavi Dave
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Jaahnavi Dave
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Mathieu J. F. Crupi
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Mathieu J. F. Crupi
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Justin Mayer
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Victoria Taylor
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Julia Petryk
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Christiano Tanese de Souza
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Neil Moodie
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Jacob Lecompte Billingsley
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Bradley Austin
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Nicole Cormack
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Natalie Blamey
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Reza Rezaei
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Reza Rezaei
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Curtis W. McCloskey
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Curtis W. McCloskey
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Emily E. F. Fekete
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Emily E. F. Fekete
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Harsimrat K. Birdi
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Harsimrat K. Birdi
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Serge Neault
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Serge Neault
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Taylor R. Jamieson
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Taylor R. Jamieson
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Brenna Wylie
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Sarah Tucker
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Taha Azad
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Taha Azad
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Barbara Vanderhyden
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Barbara Vanderhyden
- Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, ON, Canada
- Lee-Hwa Tai
- Department of Immunology and Cell Biology, Université de Sherbrooke, Sherbrooke, QC, Canada
- John C. Bell
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- John C. Bell
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- Carolina S. Ilkow
- Ottawa Hospital Research Institute, The Ottawa Hospital, Ottawa, ON, Canada
- Carolina S. Ilkow
- Department of Biochemistry, Microbiology and Immunology, University of Ottawa, Ottawa, ON, Canada
- DOI
- https://doi.org/10.3389/fimmu.2023.1099459
- Journal volume & issue
-
Vol. 14
Abstract
IntroductionAdipocytes in the tumour microenvironment are highly dynamic cells that have an established role in tumour progression, but their impact on anti-cancer therapy resistance is becoming increasingly difficult to overlook.MethodsWe investigated the role of adipose tissue and adipocytes in response to oncolytic virus (OV) therapy in adipose-rich tumours such as breast and ovarian neoplasms.ResultsWe show that secreted products in adipocyte-conditioned medium significantly impairs productive virus infection and OV-driven cell death. This effect was not due to the direct neutralization of virions or inhibition of OV entry into host cells. Instead, further investigation of adipocyte secreted factors demonstrated that adipocyte-mediated OV resistance is primarily a lipid-driven phenomenon. When lipid moieties are depleted from the adipocyte-conditioned medium, cancer cells are re-sensitized to OV-mediated destruction. We further demonstrated that blocking fatty acid uptake by cancer cells, in a combinatorial strategy with virotherapy, has clinical translational potential to overcome adipocyte-mediated OV resistance.DiscussionOur findings indicate that while adipocyte secreted factors can impede OV infection, the impairment of OV treatment efficacy can be overcome by modulating lipid flux in the tumour milieu.
Keywords