OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection.
OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection.
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OX40触发调节性T细胞抑制块并促进肿瘤排斥。
DOI：
10.1084/jem.20071341
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发表时间：
2008-04-14
影响因子：
15.3
通讯作者：
Colombo, Mario P.
中科院分区：
文献类型：
--
作者：
Piconese, Silvia;Valzasina, Barbara;Colombo, Mario P.
调节性T（T reg）细胞是癌症免疫治疗的主要障碍，并且它们的消耗迅速诱导外周前体转化为T reg细胞。我们表明，T reg细胞可以通过OX 40触发功能失活。在肿瘤中，绝大多数CD 4 + T细胞是Foxp 3+和OX 40 bright。然而，肿瘤内注射激动剂抗OX 40单克隆抗体（mAb）OX 86，而不是抗CD 25 mAb，在80%的小鼠中诱导肿瘤排斥反应，这种作用被CD 8耗竭所消除。在肿瘤内OX 40触发后，增加数量的浸润树突状细胞（DC）迁移到引流淋巴结并产生新一波肿瘤特异性细胞毒性T淋巴细胞，如通过淋巴结CD 8 + T淋巴细胞的四聚体和CD 44染色所检测到的。用OX 40缺陷型T reg细胞和野生型（WT）效应T细胞或相互组合重建的荷瘤Rag 1敲除（KO）小鼠表明，T reg和效应T细胞必须通过OX 40触发肿瘤被排斥。因此，接受肿瘤内共注射OX 86和卵清蛋白蛋白的WT而不是OX 40-KO小鼠能够逆转过继转移的OX 40感受态OTII T淋巴细胞的肿瘤诱导的耐受化。总之，OX 40介导的T reg细胞功能失活释放附近的DC，使它们能够诱导适应性免疫应答。此外，已知的适应性信号向活化的T细胞的0X 40依赖性递送通过同时的T reg细胞抑制而增强。因此，0X 40触发具有汇聚以介导肿瘤排斥的多种效应。
Regulatory T (T reg) cells are the major obstacle to cancer immunotherapy, and their depletion promptly induces conversion of peripheral precursors into T reg cells. We show that T reg cells can be functionally inactivated by OX40 triggering. In tumors, the vast majority of CD4+ T cells are Foxp3+ and OX40bright. However, intratumor injection of the agonist anti-OX40 monoclonal antibody (mAb) OX86, but not anti-CD25 mAb, induces tumor rejection in 80% of mice, an effect that is abrogated by CD8 depletion. Upon intratumor OX40 triggering, increased numbers of infiltrating dendritic cells (DCs) migrate to draining lymph nodes and generate a new wave of tumor-specific cytotoxic T lymphocytes, as detected by tetramer and CD44 staining of node CD8+ T lymphocytes. Tumor-bearing Rag1-knockout (KO) mice reconstituted with OX40-deficient T reg cells and wild-type (WT) effector T cells, or the reciprocal combination, showed that both T reg and effector T cells must be triggered via OX40 for the tumor to be rejected. Accordingly, WT but not OX40-KO mice receiving intratumor coinjection of OX86 and ovalbumin protein were able to revert tumor-induced tolerization of adoptively transferred OX40-competent OTII T lymphocytes. In conclusion, OX40-mediated inactivation of T reg cell function unleashes nearby DCs, allowing them to induce an adaptive immune response. In addition, the known OX40-dependent delivery of fitness signals to activated T cells is boosted by concurrent T reg cell inhibition. OX40 triggering thus has multiple effects that converge to mediate tumor rejection.
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影响因子：
11.2
作者：
Dercamp, C;Chemin, K;Vicari, AP
通讯作者：
Vicari, AP
影响因子：
11.2
作者：
Cohen, AD;Diab, A;Houghton, AN
通讯作者：
Houghton, AN
影响因子：
4.4
作者：
Gramaglia, I;Jember, A;Croft, M
通讯作者：
Croft, M
用激动性抗GITR mAb治疗晚期肿瘤及其对肿瘤浸润Foxp3+CD25+CD4+调节T细胞的影响。
影响因子：
15.3
作者：
Ko, K;Yamazaki, S;Nakamura, K;Nishioka, T;Hirota, K;Yamaguchi, T;Shimizu, J;Nomura, T;Chiba, T;Sakaguchi, S
通讯作者：
Sakaguchi, S
影响因子：
64.5
作者：
Förster, R;Schubel, A;Lipp, M
通讯作者：
Lipp, M