Critical Roles of Chemoresistant Effector and Regulatory T Cells in Antitumor Immunity after Lymphodepleting Chemotherapy
Critical Roles of Chemoresistant Effector and Regulatory T Cells in Antitumor Immunity after Lymphodepleting Chemotherapy
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DOI：
10.4049/jimmunol.1401468
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发表时间：
2015-07-15
影响因子：
4.4
通讯作者：
Narita, Ichiei
中科院分区：
文献类型：
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作者：
Saida, Yu;Watanabe, Satoshi;Narita, Ichiei
抗肿瘤免疫增强细胞毒性淋巴细胞清除疗法。连续转移的幼稚和效应T细胞广泛增殖，并在淋巴细胞减少的受体中显示出增强的抗肿瘤作用。尽管淋巴细胞耗竭对转移的供体T细胞的影响已经得到了很好的评价，但其对受体T细胞的影响在很大程度上是未知的。目前的研究表明，淋巴细胞减少受者的调节性T细胞和效应性CD 8（+）T细胞在淋巴细胞耗竭后抗肿瘤免疫的发展中起着关键作用。环磷酰胺（CPA）处理比其他细胞毒性药物更有效地消耗淋巴细胞;然而，在CPA处理的淋巴细胞减少小鼠中，CD 4（+）CD 25（+）Foxp 3（+）T淋巴细胞百分比显著增加。CPA治疗后这些化学抗性T细胞的消耗和初始CD 4（+）T细胞的转移增强了抗肿瘤免疫力，并显着抑制肿瘤进展。进一步的分析表明，受体CD 8（+）T细胞负责这种增强。使用Rag 2（-/-）小鼠或CPA处理后受体CD 8（+）T细胞的耗竭消除了CPA处理的重建小鼠中抗肿瘤作用的增强。供体CD 4（+）T细胞的转移增强了CD 8（+）T细胞的增殖和来自淋巴细胞减少的受体的肿瘤特异性CD 8（+）T细胞的致敏。这些结果突出了受体细胞在癌症免疫疗法中存活的细胞毒性方案的重要性。
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(+) Foxp3(+) 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.