RNF43 p.G659fs 通过 PI3K/AKT/mTOR 信号通路和 HLA-E 上调导致 MSI-high 结直肠癌中 NK 细胞功能障碍
RNF43 p.G659fs leads to natural killer cell dysfunction in MSI-high colorectal cancer through PI3K/AKT/mTOR signaling and HLA-E up-regulation.
CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
GITR 连接改善 anti-PD1 介导的人 MMR 功能完整型结直肠癌肿瘤来源 T 细胞的恢复
英文原题：GITR Ligation Improves Anti-PD1-Mediated Restoration of Human MMR-Proficient Colorectal Carcinoma Tumor-Derived T Cells.
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GITR Ligation Improves Anti-PD1-Mediated Restoration of Human MMR-Proficient Colorectal Carcinoma Tumor-Derived T Cells.
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研究概要
GITR 在 pMMR CRC 和 CRLM 的 CD4+和 CD8+TIL 上过表达。GITR 的激动剂靶向可增强离体人 TIL 功能，因此可能成为原发性 pMMR CRC 和 CRLM 新型单药或联合免疫治疗的有前景的方法。
研究思路结论见上方概要
目的
与错配修复缺陷型结直肠癌（CRC）相比，错配修复正常（pMMR）CRC对免疫检查点阻断无应答。我们通过糖皮质激素诱导的肿瘤坏死因子受体相关蛋白（GITR）研究了免疫检查点刺激对从pMMR原发性CRC和肝转移（CRLM）中分离的人TIL（肿瘤浸润淋巴细胞）离体功能的影响。
方法
使用132例pMMR原发性CRC或CRLM患者切除肿瘤、邻近组织和外周血单个核细胞（PBMC）中的淋巴细胞，我们检测了GITR表达以及重组GITR连接的体外T细胞激动活性。
结果
在这里，我们表明与其他刺激性免疫检查点（4-1BB、OX40）相比，GITR在TIL上过表达。与PBMC和邻近组织相比，其在TIL中的表达增强。在CD4+ TIL中，GITR表达主要由CD45RA- FoxP3 hi活化调节性T细胞表达。在CD8+ TIL中，GITR主要表达于功能耗竭和推测肿瘤反应性的CD103+ CD39+ TIL上。引人注目的是，重组GITRL通过显著增加CD4+和CD8+ TIL数量，重新激活了离体TIL反应。与GITRL单药治疗相比，GITRL和nivolumab（抗PD1）双重治疗增强了CD8+ TIL扩增。此外，GITRL/抗PD1双重治疗进一步改善了抗PD1介导的原发性CRC耗竭CD8 TIL干扰素γ分泌的重新激活。
展开英文摘要原文
METHODS
Using lymphocytes from resected tumor, adjacent tissues, and peripheral blood mononuclear cells (PBMC) of 132 pMMR primary CRC or CRLM patients, we determined GITR expression and the in vitro T-cell agonistic activity of recombinant GITR ligation.
RESULTS
Here, we show that GITR was overexpressed on TIL when compared with other stimulatory immune checkpoints (4-1BB, OX40). Its expression was enhanced in TIL compared with PBMC and adjacent tissues. Among CD4 + TIL, GITR expression was primarily expressed by CD45RA - FoxP3 hi activated regulatory T cells. Within CD8 + TIL, GITR was predominantly expressed on functionally exhausted and putative tumor-reactive CD103 + CD39 + TIL. Strikingly, recombinant GITRL reinvigorated ex vivo TIL responses by significantly enhancing CD4 + and CD8 + TIL numbers. Dual treatment with GITRL and nivolumab (anti-PD1) enhanced CD8 + TIL expansion compared with GITRL monotherapy. Moreover, GITRL/anti-PD1 dual therapy further improved anti-PD1-mediated reinvigoration of interferon gamma secretion by exhausted CD8 TIL from primary CRC.
CONCLUSIONS
GITR is overexpressed on CD4 + and CD8 + TIL from pMMR CRC and CRLM. Agonistic targeting of GITR enhances ex vivo human TIL functionality and may therefore be a promising approach for novel monotherapy or combined immunotherapies in primary pMRR CRC and CRLM.
论文信息
- 作者
- Rakké YS、Campos Carrascosa L、van Beek AA、de Ruiter V、van Gemerden RS、Doukas M、Doornebosch PG、Vermaas M
- 第一作者单位
- Department of Surgery, Erasmus MC-University Medical Center, Rotterdam, the Netherlands.Netherlands
- 通讯作者单位
- Department of Gastroenterology and Hepatology, Erasmus MC-University Medical Center, Rotterdam, the Netherlands. Electronic address: d.sprengers@erasmusmc.nl.Netherlands
- 期刊
- Cellular and molecular gastroenterology and hepatology2023
- 原文标识
- PubMed 36155259 · DOI 10.1016/j.jcmgh.2022.09.007
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