OX40 triggering blocks suppression by regulatory T cells and facilitates tumor rejection
نویسندگان
چکیده
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 OX40(bright). 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.
منابع مشابه
Correction Ox40 Triggering Blocks Suppression by Regulatory T Cells and Facilitates Tumor Rejection
The authors regret that two of the fl ow cytometry histograms in Fig. 3 C were inadvertently duplicated. The corrected fi gure and its legend appear below. Figure 3. Tumor-infi ltrating T reg cells express functional OX40. (A) TILs were purifi ed from a pool of CT26 tumor nodules, and the CD4 + cell population was analyzed by fl ow cytometry (percentages are shown). As controls, CD4 + T cells w...
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ورودعنوان ژورنال:
- The Journal of Experimental Medicine
دوره 205 شماره
صفحات -
تاریخ انتشار 2008