Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance
Constitutive IDO1 Expression in Human Tumors Is Driven by Cyclooxygenase-2 and Mediates Intrinsic Immune Resistance
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DOI：
10.1158/2326-6066.cir-16-0400
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发表时间：
2017-08-01
影响因子：
10.1
通讯作者：
van den Eynde, Benio T. J.
中科院分区：
文献类型：
--
作者：
Hennequart, Marc;Pilotte, Luc;van den Eynde, Benio T. J.
肿瘤使用各种机制来避免免疫破坏。环氧合酶-2（考克斯-2）表达可能是黑色素瘤免疫抑制的驱动因素，但其相关机制仍不清楚。在这里，我们表明，考克斯-2的表达驱动吲哚胺2，3-双加氧酶1（IDO 1）在人类肿瘤细胞的组成型表达。IDO 1是一种降解色氨酸的免疫抑制酶。在一系列的7种人类肿瘤细胞系中，组成性IDO 1表达依赖于考克斯-2和前列腺素E2（PGE（2）），后者通过EP受体自分泌信号，通过PKC和PI 3 K途径激活IDO 1。考克斯-2表达本身依赖于MAPK通路，因此MAPK通路间接控制IDO 1表达。大多数这些肿瘤携带PI 3 K或MAPK致癌突变，这可能有利于组成型IDO 1表达。塞来昔布治疗促进了用人同种异体淋巴细胞重建的免疫缺陷小鼠中表达IDO 1的人肿瘤异种移植物的免疫排斥。这种效应与卵巢SKOV 3肿瘤中IDO 1表达减少以及CD 3（+）和CD 8（+）细胞浸润增加有关。我们的研究结果突出了考克斯-2在人肿瘤组成型IDO 1表达中的作用，并证实了考克斯-2抑制剂通过减少组成型IDO 1表达来提高癌症免疫治疗的功效，组成型IDO 1表达导致“冷”肿瘤中缺乏T细胞浸润，而“冷”肿瘤对免疫治疗没有反应。Cancer Immunol Res; 5（8）; 695-709. (C)2017年AACR。
Tumors use various mechanisms to avoid immune destruction. Cyclooxygenase-2 (COX-2) expression may be a driver of immune suppression in melanoma, but the mechanisms involved remain elusive. Here, we show that COX-2 expression drives constitutive expression of indoleamine 2,3-dioxygenase 1 (IDO1) in human tumor cells. IDO1 is an immunosuppressive enzyme that degrades tryptophan. In a series of seven human tumor lines, constitutive IDO1 expression depends on COX-2 and prostaglandin E2 (PGE(2)), which, upon autocrine signaling through the EP receptor, activates IDO1 via the PKC and PI3K pathways. COX-2 expression itself depends on the MAPK pathway, which therefore indirectly controls IDO1 expression. Most of these tumors carry PI3K or MAPK oncogenic mutations, which may favor constitutive IDO1 expression. Celecoxib treatment promoted immune rejection of IDO1-expressing human tumor xenografts in immunodeficient mice reconstituted with human allogeneic lymphocytes. This effect was associated with a reduced expression of IDO1 in those ovarian SKOV3 tumors and an increased infiltration of CD3(+) and CD8(+) cells. Our results highlight the role of COX-2 in constitutive IDO1 expression by human tumors and substantiate the use of COX-2 inhibitors to improve the efficacy of cancer immunotherapy, by reducing constitutive IDO1 expression, which contributes to the lack of T-cell infiltration in "cold" tumors, which fail to respond to immunotherapy. Cancer Immunol Res; 5(8); 695-709. (C) 2017 AACR.