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A reduction of recipient regulatory T cells by cyclophosphamide contributes to an anti‐tumor effect of nonmyeloablative allogeneic stem cell transplantation in mice
Author(s) -
Takeuchi Ario,
Eto Masatoshi,
Yamada Hisakata,
Tatsugami Katsunori,
Naito Seiji,
Yoshikai Yasunobu
Publication year - 2011
Publication title -
international journal of cancer
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 2.475
H-Index - 234
eISSN - 1097-0215
pISSN - 0020-7136
DOI - 10.1002/ijc.26009
Subject(s) - cyclophosphamide , il 2 receptor , foxp3 , spleen , adoptive cell transfer , transplantation , cancer research , immunology , stem cell , medicine , t cell , immune system , biology , chemotherapy , microbiology and biotechnology
We have recently established a unique model system of nonmyeloablative allogeneic stem cell transplantation (SCT) for treatment of murine solid tumors, based on cyclophosphamide‐induced tolerance. An injection of allogeneic donor spleen cells and bone marrow cells (BMC) followed by cyclophosphamide treatment induced a stable mixed chimerism with long lasting tolerance to the allografts. A donor lymphocyte infusion (DLI) in the cyclophosphamide‐induced tolerant mice exerted strong anti‐tumor effects on an MBT‐2 murine bladder tumor, MBT‐2 via their graft versus tumor (GVT) activity. In the present study, we determined whether a cyclophosphamide‐induced reduction of naturally occurring regulatory T cells (Tregs) was associated with the anti‐tumor activity in our nonmyeloablative SCT system. The number of recipient CD4+ CD25+ Foxp3+ Tregs significantly decreased 3 days after an intraperitoneal injection of cyclophosphamide in C3H/HeN mice that had been injected with spleen cells and BMC of donor AKR/J mice, compared with the number of CD4+ CD25+ Foxp3‐ T cells. An adoptive transfer of CD4+ CD25+ T cells from naïve C3H/He x AKR/J F1 mice into recipient mice 1 day after DLI significantly suppressed the expansion and IFN‐γ production of host‐reactive donor CD4+T cells and hampered the MBT‐2 anti‐tumor activity when compared with the transfer of CD4+ CD25‐ T cells. These results indicated that cyclophosphamide‐induced reduction of recipient Tregs is associated with retardation of tumor progression via the expansion of host‐reactive donor T cells and IFN‐γ production after DLI in our nonmyeloablative SCT system.