GADD45β Loss Ablates Innate Immunosuppression in Cancer.
GADD45β Loss Ablates Innate Immunosuppression in Cancer.
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DOI：
10.1158/0008-5472.can-17-1833
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发表时间：
2018-03-01
期刊：
影响因子：
11.2
通讯作者：
Franzoso G
中科院分区：
文献类型：
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作者：
Verzella D;Bennett J;Fischietti M;Thotakura AK;Recordati C;Pasqualini F;Capece D;Vecchiotti D;D'Andrea D;Di Francesco B;De Maglie M;Begalli F;Tornatore L;Papa S;Lawrence T;Forbes SJ;Sica A;Alesse E;Zazzeroni F;Franzoso G
T细胞排斥肿瘤微环境（TME）是克服免疫逃逸的主要障碍。在这里，我们确定了一种由NF-κB效应分子GADD45β控制的髓内机制，该机制限制肿瘤相关炎症和T细胞转运到肿瘤中。在各种难以免疫治疗的实体癌模型中，包括肝细胞癌（HCC）和卵巢腺癌，髓细胞中Gadd45b的抑制恢复了促炎肿瘤相关巨噬细胞（TAM）的激活和瘤内免疫浸润，从而减少了肿瘤的发生。我们的结果为解释GADD45B表达升高在大多数人类癌症中导致不良临床结果的临床证据提供了基础。此外，他们提出了GADD45β中的治疗靶点，用于重新编程TAM以克服TME的免疫抑制和T细胞排斥。
T cell exclusion from the tumour microenvironment (TME) is a major barrier to overcoming immune escape. Here we identify a myeloid-intrinsic mechanism governed by the NF-κB effector molecule GADD45β that restricts tumour-associated inflammation and T cell trafficking into tumours. In various models of solid cancers refractory to immunotherapies, including hepatocellular carcinoma (HCC) and ovarian adenocarcinoma, Gadd45b inhibition in myeloid cells restored activation of pro-inflammatory tumour-associated macrophages (TAM) and intratumoural immune infiltration, thereby diminishing oncogenesis. Our results provide a basis to interpret clinical evidence that elevated expression of GADD45B confers poor clinical outcomes in most human cancers. Further, they suggest a therapeutic target in GADD45β for re-programming TAM to overcome immunosuppression and T cell exclusion from the TME.