Journal article
Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy
Cancer Immunology, Immunotherapy, Vol.58(8), pp.1219-1228
2009
Abstract
Tumor cell death potentially engages with the immune system. However, the efficacy of anti-tumor chemotherapy may be limited by tumor-driven immunosuppression, e.g., through CD25+ regulatory T cells. We addressed this question in a mouse model of mesothelioma by depleting or reconstituting CD25+ regulatory T cells in combination with two different chemotherapeutic drugs. We found that the efficacy of cyclophosphamide to eradicate established tumors, which has been linked to regulatory T cell depletion, was negated by adoptive transfer of CD25+ regulatory T cells. Analysis of post-chemotherapy regulatory T cell populations revealed that cyclophosphamide depleted cycling (Ki-67hi) T cells, including foxp3+ regulatory CD4+ T cells. Ki-67hi CD4+ T cells expressed increased levels of two markers, TNFR2 and ICOS, that have been associated with a maximally suppressive phenotype according to recently published studies. This suggest that cyclophosphamide depletes a population of maximally suppressive regulatory T cells, which may explain its superior anti-tumor efficacy in our model. Our data suggest that regulatory T cell depletion could be used to improve the efficacy of anti-cancer chemotherapy regimens. Indeed, we observed that the drug gemcitabine, which does not deplete cycling regulatory T cells, eradicates established tumors in mice only when CD25+ CD4+ T cells are concurrently depleted. Cyclophosphamide could be used to achieve regulatory T cell depletion in combination with chemotherapy.
Details
- Title
- Tumor eradication after cyclophosphamide depends on concurrent depletion of regulatory T cells: a role for cycling TNFR2-expressing effector-suppressor T cells in limiting effective chemotherapy
- Authors/Creators
- R.G. Most (Author/Creator)A.J. Currie (Author/Creator) - The University of Western AustraliaS. Mahendran (Author/Creator) - The University of Western AustraliaA. Prosser (Author/Creator) - The University of Western AustraliaA. Darabi (Author/Creator) - Lund UniversityB.W.S. Robinson (Author/Creator) - The University of Western AustraliaA.K. Nowak (Author/Creator) - The University of Western AustraliaR.A. Lake (Author/Creator) - The University of Western Australia
- Publication Details
- Cancer Immunology, Immunotherapy, Vol.58(8), pp.1219-1228
- Publisher
- Springer Science and Business Media Deutschland GmbH
- Identifiers
- 991005541130207891
- Copyright
- © 2008 Springer-Verlag.
- Murdoch Affiliation
- Murdoch University
- Language
- English
- Resource Type
- Journal article
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- Collaboration types
- Industry collaboration
- Domestic collaboration
- International collaboration
- Citation topics
- 1 Clinical & Life Sciences
- 1.6 Immunology
- 1.6.487 Regulatory T Cells
- Web Of Science research areas
- Immunology
- Oncology
- ESI research areas
- Immunology