Journal article
Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth
PLoS ONE, Vol.4(9), e6982
2009
Abstract
Background: Anti-cancer chemotherapy can be simultaneously lymphodepleting and immunostimulatory. Pre-clinical models clearly demonstrate that chemotherapy can synergize with immunotherapy, raising the question how the immune system can be mobilized to generate anti-tumor immune responses in the context of chemotherapy. Methods and Findings: We used a mouse model of malignant mesothelioma, AB1-HA, to investigate T cell-dependent tumor resolution after chemotherapy. Established AB1-HA tumors were cured by a single dose of cyclophosphamide in a CD8 T cell- and NK cell-dependent manner. This treatment was associated with an IFN-α/β response and a profound negative impact on the anti-tumor and total CD8 T cell responses. Despite this negative effect, CD8 T cells were essential for curative responses. The important effector molecules used by the anti-tumor immune response included IFN-γ and TRAIL. The importance of TRAIL was supported by experiments in nude mice where the lack of functional T cells could be compensated by agonistic anti-TRAIL-receptor (DR5) antibodies. Conclusion: The data support a model in which chemotherapy sensitizes tumor cells for T cell-, and possibly NK cell-, mediated apoptosis. A key role of tumor cell sensitization to immune attack is supported by the role of TRAIL in tumor resolution and explains the paradox of successful CD8 T cell-dependent anti-tumor responses in the absence of CD8 T cell expansion.
Details
- Title
- Cyclophosphamide chemotherapy sensitizes tumor cells to TRAIL-dependent CD8 T cell-mediated immune attack resulting in suppression of tumor growth
- Authors/Creators
- R.G. van der Most (Author/Creator) - The University of Western AustraliaA.J. Currie (Author/Creator) - The University of Western AustraliaA.L. Cleaver (Author/Creator) - The University of Western AustraliaJ. Salmons (Author/Creator) - The University of Western AustraliaA.K. Nowak (Author/Creator) - The University of Western AustraliaS. Mahendran (Author/Creator) - The University of Western AustraliaI. Larma (Author/Creator) - The University of Western AustraliaA. Prosser (Author/Creator) - The University of Western AustraliaB.W.S. Robinson (Author/Creator) - The University of Western AustraliaM.J. Smyth (Author/Creator) - Peter MacCallum Cancer CentreA.A. Scalzo (Author/Creator) - Lions Eye InstituteM.A. Degli-Esposti (Author/Creator) - Lions Eye InstituteR.A. Lake (Author/Creator) - The University of Western Australia
- Publication Details
- PLoS ONE, Vol.4(9), e6982
- Publisher
- Public Library of Science
- Identifiers
- 991005541150307891
- Copyright
- © 2009 van der Most et al.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
- Note
- This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
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- Citation topics
- 1 Clinical & Life Sciences
- 1.6 Immunology
- 1.6.214 Checkpoint Inhibition
- Web Of Science research areas
- Immunology
- ESI research areas
- Immunology