miR-153 suppresses IDO1 expression and enhances CAR T cell immunotherapy.
miR-153 suppresses IDO1 expression and enhances CAR T cell immunotherapy.
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miR-153抑制IDO1表达并增强CAR T细胞免疫治疗
DOI：
10.1186/s13045-018-0600-x
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发表时间：
2018-04-23
影响因子：
28.5
通讯作者：
Li Y
中科院分区：
文献类型：
--
作者：
Huang Q;Xia J;Wang L;Wang X;Ma X;Deng Q;Lu Y;Kumar M;Zhou Z;Li L;Zeng Z;Young KH;Yi Q;Zhang M;Li Y
吲哚胺2，3-双加氧酶1（IDO 1）催化色氨酸转化为犬尿氨酸的第一步和限速步骤。嵌合抗原受体（CAR）T细胞是具有靶向肿瘤相关抗原的重组受体的T细胞。美国食品和药物管理局已批准靶向CD 19的CAR T细胞用于治疗晚期B细胞白血病和淋巴瘤。然而，实体瘤中的CAR T细胞治疗受到多重障碍的阻碍。临床前和临床研究表明，组合免疫检查点阻断和IDO 1抑制提供了针对癌症的持久治疗功效。然而，尚未尝试IDO 1抑制和CAR T的组合。我们分析了结肠癌细胞中miR-153对IDO 1的下调以及IDO 1和miR-153表达与结直肠患者生存的相关性。我们产生靶向表皮生长因子受体变体III的CAR T细胞，并通过杀伤试验和异种移植物中测量它们对有或没有miR-153过表达的结肠癌细胞的肿瘤杀伤作用。IDO 1在结直肠肿瘤中高度表达，与患者生存率呈负相关。miR-153通过靶向IDO 1在结肠癌细胞中的3′非翻译区直接抑制IDO 1表达;然而，miR-153过表达不影响癌细胞存活、凋亡和集落形成。当结肠癌细胞被CAR T细胞靶向时，肿瘤细胞内的miR-153过表达显著增强了体外T细胞杀伤并抑制了小鼠异种移植肿瘤的生长。这些发现表明，miR-153抑制结肠癌细胞中IDO 1的表达，并且是一种增强CAR T细胞免疫治疗的肿瘤抑制性miRNA。这项研究支持IDO 1抑制剂和CAR T细胞在治疗实体瘤中的组合使用。本文的在线版本（10.1186/s13045-018-0600-x）包含补充材料，可供授权用户使用。
Indoleamine 2,3-dioxygenase 1 (IDO1) catalyzes the first and rate-limiting step in converting tryptophan to kynurenine. Chimeric antigen receptor (CAR) T cells are T cells with recombinant receptors targeting tumor-associated antigens. The Food and Drug Administration has approved CAR T cells that target CD19 for treatment of advanced B cell leukemia and lymphoma. However, CAR T cell therapy in solid tumors has been hampered by multiple obstacles. Preclinical and clinical studies suggest that combinatorial immune checkpoint blockade and IDO1 inhibition provide durable therapeutic efficacy against cancer. Yet, the combination of IDO1 inhibition and CAR T has not been attempted. We analyze IDO1 downregulation by miR-153 in colon cancer cells and the association of IDO1 and miR-153 expression with colorectal patient survival. We generate CAR T cells targeting the epidermal growth factor receptor variant III and measure their tumor killing effects against colon cancer cells with or without miR-153 overexpression by killing assays and in xenografts. IDO1 is highly expressed in colorectal tumors and is inversely associated with patient survival. miR-153 directly inhibits IDO1 expression by targeting its 3′ untranslated region in colon cancer cells; yet, miR-153 overexpression does not affect cancer cell survival, apoptosis, and colony formation. When colon cancer cells are targeted by CAR T cells, miR-153 overexpression within tumor cells significantly enhances T cell killing in vitro and suppresses xenograft tumor growth in mice. These findings indicate that miR-153 inhibits IDO1 expression in colon cancer cells and is a tumor-suppressive miRNA that enhances CAR T cell immunotherapy. This study supports the combinatorial use of IDO1 inhibitors and CAR T cells in treating solid tumors. The online version of this article (10.1186/s13045-018-0600-x) contains supplementary material, which is available to authorized users.
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影响因子：
64.8
作者：
Baek, Daehyun;Villen, Judit;Shin, Chanseok;Camargo, Fernando D.;Gygi, Steven P.;Bartel, David P.
通讯作者：
Bartel, David P.
影响因子：
11.5
作者：
Brandacher, G;Perathoner, A;Amberger, A
通讯作者：
Amberger, A
黑色素瘤肿瘤微环境中PD-L1，IDO和T（REGS）的上调由CD8（+）T细胞驱动。
影响因子：
17.1
作者：
Spranger S;Spaapen RM;Zha Y;Williams J;Meng Y;Ha TT;Gajewski TF
通讯作者：
Gajewski TF
DOI：
10.1038/nrc.2016.97
发表时间：
2016-08-23
期刊：
Nature reviews. Cancer
影响因子：
--
作者：
Fesnak AD;June CH;Levine BL
通讯作者：
Levine BL
影响因子：
10.1
作者：
Theate, Ivan;van Baren, Nicolas;Van den Eynde, Benoit J.
通讯作者：
Van den Eynde, Benoit J.