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
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⁺ reg...
Saved in:
Published in | Cancer Immunology, Immunotherapy Vol. 58; no. 8; pp. 1219 - 1228 |
---|---|
Main Authors | , , , , , , , |
Format | Journal Article |
Language | English |
Published |
Berlin/Heidelberg
Berlin/Heidelberg : Springer-Verlag
01.08.2009
Springer-Verlag Springer Springer Nature B.V |
Subjects | |
Online Access | Get full text |
Cover
Loading…
Summary: | 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. |
---|---|
Bibliography: | http://dx.doi.org/10.1007/s00262-008-0628-9 ObjectType-Article-1 SourceType-Scholarly Journals-1 ObjectType-Feature-2 content type line 23 |
ISSN: | 0340-7004 1432-0851 1432-0851 |
DOI: | 10.1007/s00262-008-0628-9 |