Glial TIM-3 Modulates Immune Responses in the Brain Tumor Microenvironment.
Glial TIM-3 Modulates Immune Responses in the Brain Tumor Microenvironment.
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DOI：
10.1158/0008-5472.can-19-2834
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发表时间：
2020-05-01
期刊：
影响因子：
11.2
通讯作者：
Park EJ
中科院分区：
文献类型：
--
作者：
Kim HS;Chang CY;Yoon HJ;Kim KS;Koh HS;Kim SS;Lee SJ;Kane LP;Park EJ
T 细胞免疫球蛋白和含有粘蛋白结构域的分子 3 (TIM-3) 是癌症的潜在免疫治疗靶点，已被证明以依赖于环境的方式表现出不同的特征。因此，在给定情况下描述 TIM-3 的精确功能特征将很有用。在这里，我们报告神经胶质 TIM-3 在脑肿瘤微环境中显示出独特的特性。在原位小鼠神经胶质瘤模型中，TIM-3 在生长的肿瘤细胞及其周围细胞（包括神经胶质细胞和 T 细胞）上表达。 TIM-3 的表达模式与肿瘤暴露和肿瘤浸润神经胶质细胞中其他免疫检查点分子的表达模式不同。神经胶质瘤模型荷瘤半球和对侧半球细胞的比较表明，肿瘤浸润性 CD11b+CD45mid 胶质细胞中 TIM-3 表达较低，但肿瘤浸润性 CD8+ T 细胞中 TIM-3 表达较高。在具有细胞内信号传导缺陷的 TIM-3 突变小鼠和 Cre 诱导型 TIM-3 小鼠中，TIM-3 影响脑肿瘤的原代胶质细胞暴露条件培养基 (CM) 中几种免疫相关分子的表达，包括 iNOS 和 PD-L1。此外，在脑肿瘤 CM 或 Pam3CSK4 暴露的神经胶质细胞中，TIM-3 被 TLR2 交叉调节，但不被 TLR4 交叉调节。此外，暴露于肿瘤CM后，与TIM-3缺陷型神经胶质细胞共培养的T细胞中IFNγ的产生量低于与正常神经胶质细胞共培养的T细胞。总的来说，这些发现表明神经胶质TIM-3对脑肿瘤有积极而独特的反应，并发挥特定的细胞内和细胞间免疫调节作用，这可能与脑肿瘤微环境中T细胞上的TIM-3不同。 TIM-3 通常被认为是 T 细胞检查点受体。这项研究证明了 TIM-3 在介导胶质母细胞瘤中骨髓细胞反应中的作用。
T-cell immunoglobulin and mucin domain–containing molecule 3 (TIM-3), a potential immunotherapeutic target for cancer, has been shown to display diverse characteristics in a context-dependent manner. Thus, it would be useful to delineate the precise functional features of TIM-3 in a given situation. Here, we report that glial TIM-3 shows distinctive properties in the brain tumor microenvironment. TIM-3 was expressed on both growing tumor cells and their surrounding cells including glia and T cells in an orthotopic mouse glioma model. The expression pattern of TIM-3 was distinct from those of other immune checkpoint molecules in tumor-exposed and tumor-infiltrating glia. Comparison of cells from tumor-bearing and contralateral hemispheres of a glioma model showed that TIM-3 expression was lower in tumor-infiltrating CD11b+CD45mid glial cells but higher in tumor-infiltrating CD8+ T cells. In TIM-3 mutant mice with intracellular signaling defects and Cre-inducible TIM-3 mice, TIM-3 affected the expression of several immune-associated molecules including iNOS and PD-L1 in primary glia-exposed conditioned media (CM) from brain tumors. Further, TIM-3 was cross-regulated by TLR2, but not by TLR4, in brain tumor CM- or Pam3CSK4-exposed glia. In addition, following exposure to tumor CM, IFNγ production was lower in T cells cocultured with TIM-3–defective glia than with normal glia. Collectively, these findings suggest that glial TIM-3 actively and distinctively responds to brain tumor, and plays specific intracellular and intercellular immunoregulatory roles that might be different from TIM-3 on T cells in the brain tumor microenvironment. TIM-3 is typically thought of as a T-cell checkpoint receptor. This study demonstrates a role for TIM-3 in mediating myeloid cell responses in glioblastoma.