STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation.
STING Promotes the Growth of Tumors Characterized by Low Antigenicity via IDO Activation.
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DOI：
10.1158/0008-5472.can-15-1456
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发表时间：
2016-04-15
期刊：
影响因子：
11.2
通讯作者：
Mellor AL
中科院分区：
文献类型：
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作者：
Lemos H;Mohamed E;Huang L;Ou R;Pacholczyk G;Arbab AS;Munn D;Mellor AL
胞浆DNA传感是天然免疫应答过程中的一个重要过程，激活干扰素基因刺激物(STING)接头，诱导干扰素I型(IFN-I)。在免疫原性肿瘤生长过程中，STING可激发自发免疫，因此，STING激动剂可诱导耐药肿瘤的消退。然而，DNA、STING激动剂和凋亡细胞也可以通过激活吲哚胺2，3双加氧酶(IDO)等免疫调节机制，通过STING促进耐受反应。在这里，我们证明了肿瘤微环境(TME)中由STING活性诱导的IDO活性促进了Lewis肺癌(LLC)的生长。虽然在EL4胸腺瘤的生长过程中，STING也诱导了肿瘤引流淋巴结(TDLN)中的IDO，但这一事件不足以促进肿瘤的发生。在LLC模型中，STING消融增强了TME中CD8+T细胞的浸润和肿瘤细胞的杀伤，而减少了髓系来源的抑制细胞的浸润和IL-10的产生。在STING缺陷小鼠中，CD8+T细胞的耗尽也消除了LLC肿瘤的生长劣势，表明STING信号在肿瘤发生过程中减弱了CD8+T细胞效应细胞的功能。与天然LLC肿瘤相比，STING信号不促进表达新抗原的LLC的生长，也不诱导TDLN中的IDO。同样，在这种情况下，SING未能促进B16黑色素瘤的生长或诱导TDLN中的IDO活性。因此，我们的结果表明，依赖刺痛的DNA传感如何提高抗原性低的肿瘤的耐受性状态，以及IDO抑制如何通过减弱肿瘤耐受性来克服这种状态。此外，我们的结果揭示了STING信号在癌症中的作用更加复杂，强调了TME中的固有免疫通路如何在不同的肿瘤环境中改变肿瘤的发生，这对设计有效的免疫治疗试验具有重要意义。
Cytosolic DNA sensing is an important process during the innate immune response that activates the Stimulator of Interferon Genes (STING) adaptor and induce interferon type I (IFN-I). STING incites spontaneous immunity during immunogenic tumor growth and accordingly, STING agonists induce regression of therapy-resistant tumors. However DNA, STING agonists and apoptotic cells can also promote tolerogenic responses via STING by activating immunoregulatory mechanisms such as indoleamine 2,3 dioxygenase (IDO). Here, we show that IDO activity induced by STING activity in the tumor microenvironment (TME) promoted the growth of Lewis lung carcinoma (LLC). While STING also induced IDO in tumor-draining lymph nodes (TDLNs) during EL4 thymoma growth, this event was insufficient to promote tumorigenesis. In the LLC model, STING ablation enhanced CD8+ T cell infiltration and tumor cell killing while decreasing myeloid-derived suppressor cell infiltration and IL-10 production in the TME. Depletion of CD8+ T cells also eliminated the growth disadvantage of LLC tumors in STING-deficient mice, indicating that STING signaling attenuated CD8+ T cell effector functions during tumorigenesis. In contrast to native LLC tumors, STING signaling did not promote growth of neoantigen-expressing LLC, nor did it induce IDO in TDLN. Similarly, STING failed to promote growth of B16 melanoma or to induce IDO activity in TDLN in this setting. Thus, our results show how STING-dependent DNA sensing can enhance tolerogenic states in tumors characterized by low antigenicity, and how IDO inhibition can overcome this state by attenuating tumor tolerance. Further, our results reveal a greater complexity in the role of STING signaling in cancer, underscoring how innate immune pathways in the TME modify tumorigenesis in distinct tumor settings, with implications for designing effective immunotherapy trials.