Advanced

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

van der Most, Robbert G.; Currie, Andrew J.; Mahendran, Sathish; Prosser, Amy; Darabi, Anna LU ; Robinson, Bruce W. S.; Nowak, Anna K. and Lake, Richard A. (2009) In Cancer Immunology and Immunotherapy 58(8). p.1219-1228
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-67(hi)) T cells, including foxp3(+) regulatory CD4(+) T... (More)
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-67(hi)) T cells, including foxp3(+) regulatory CD4(+) T cells. Ki-67(hi) 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. (Less)
Please use this url to cite or link to this publication:
author
organization
publishing date
type
Contribution to journal
publication status
published
subject
keywords
Mesothelioma, Chemotherapy, Tumor immunity, Regulatory CD4(+) T cells, Gemcitabine, Cyclophosphamide
in
Cancer Immunology and Immunotherapy
volume
58
issue
8
pages
1219 - 1228
publisher
Springer
external identifiers
  • wos:000266372400005
  • scopus:67349250111
ISSN
1432-0851
DOI
10.1007/s00262-008-0628-9
language
English
LU publication?
yes
id
f37e73a4-f2e3-418b-8760-31027e3b78d4 (old id 1425340)
date added to LUP
2009-07-02 10:36:48
date last changed
2017-12-10 04:10:35
@article{f37e73a4-f2e3-418b-8760-31027e3b78d4,
  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-67(hi)) T cells, including foxp3(+) regulatory CD4(+) T cells. Ki-67(hi) 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.},
  author       = {van der Most, Robbert G. and Currie, Andrew J. and Mahendran, Sathish and Prosser, Amy and Darabi, Anna and Robinson, Bruce W. S. and Nowak, Anna K. and Lake, Richard A.},
  issn         = {1432-0851},
  keyword      = {Mesothelioma,Chemotherapy,Tumor immunity,Regulatory CD4(+) T cells,Gemcitabine,Cyclophosphamide},
  language     = {eng},
  number       = {8},
  pages        = {1219--1228},
  publisher    = {Springer},
  series       = {Cancer Immunology and Immunotherapy},
  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},
  url          = {http://dx.doi.org/10.1007/s00262-008-0628-9},
  volume       = {58},
  year         = {2009},
}