Thesis or Dissertation Critical Roles of Chemoresistant Effector and Regulatory T Cells in Antitumor Immunity after Lymphodepleting Chemotherapy

Saida, Yu  ,  才田, 優

2015-09-24 , 新潟大学
学位の種類: 博士(医学). 報告番号: 甲第4064号. 学位記番号: 新大院博(医)甲第653号. 学位授与年月日: 平成27年9月24日
The Journal of Immunology. 2015, 195(2), 726-735.
Antitumor immunity is augmented by cytotoxic lymphodepletion therapies. Adoptively transferred naive and effector T cells proliferate extensively and show enhanced antitumor effects in lymphopenic recipients. Although the impact of lymphodepletion on transferred donor T cells has been well evaluated, its influence on recipient T cells is largely unknown. The current study demonstrates that both regulatory T cells (Tregs) and effector CD8^+ T cells from lymphopenic recipients play critical roles in the development of antitumor immunity after lymphodepletion. Cyclophosphamide (CPA) treatment depleted lymphocytes more efficiently than other cytotoxic agents; however, the percentage of CD4^+CD25^+ Forkhead box P3^+ Tregs was significantly increased in CPA-treated lymphopenic mice. Depletion of these chemoresistant Tregs following CPA treatment and transfer of naive CD4^+ T cells augmented the antitumor immunity and significantly suppressed tumor progression. Further analyses revealed that recipient CD8^+ T cells were responsible for this augmentation. Using Rag2^<-/-> mice or depletion of recipient CD8^+ T cells after CPA treatment abrogated the augmentation of antitumor effects in CPA-treated reconstituted mice. The transfer of donor CD4^+ T cells enhanced the proliferation of CD8^+ T cells and the priming of tumor-specific CD8^+ T cells originating from the lymphopenic recipients. These results highlight the importance of the recipient cells surviving cytotoxic regimens in cancer immunotherapies.

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