Targeting the Epidermal Growth Factor Receptor Can Counteract the Inhibition of Natural Killer Cell Function Exerted by Colorectal Tumor-Associated Fibroblasts.
Targeting the Epidermal Growth Factor Receptor Can Counteract the Inhibition of Natural Killer Cell Function Exerted by Colorectal Tumor-Associated Fibroblasts.
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DOI：
10.3389/fimmu.2018.01150
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发表时间：
2018
影响因子：
7.3
通讯作者：
Poggi A
中科院分区：
文献类型：
--
作者：
Costa D;Venè R;Benelli R;Romairone E;Scabini S;Catellani S;Rebesco B;Mastracci L;Grillo F;Minghelli S;Loiacono F;Zocchi MR;Poggi A
存在于肿瘤微环境中的间充质间质细胞（Mesenchymal stromal cells， MSC）[通常称为肿瘤相关成纤维细胞（tumor-associated fibroblasts， TAF）]可对T淋巴细胞和自然杀伤细胞（natural killer， NK）发挥免疫抑制作用，有利于肿瘤免疫逃逸。我们在结直肠癌（CRC）中分析了这一机制，发现NK细胞与TAF共培养可以阻止il -2介导的NKG2D上调。这导致nkg2d介导的CRC细胞识别受损，从而通过DNAM1或FcγRIIIA （CD16）保护NK细胞的激活。原位，TAF表达可检测水平的表皮生长因子受体（EGFR）；因此，治疗性抗egfr人源化抗体西妥昔单抗可以通过FcγRIIIA作用于NK细胞，触发TAF的抗体依赖性细胞毒性。重要的是，在肿瘤中，我们发现了含有NKp46+CD3−NK细胞的淋巴细胞浸润，富含CD16+细胞。这个群体经过IL-2的分类和培养，可以通过CD16和NKG2D触发。值得注意的是，离体NKp46+CD3−细胞能够杀死自体TAF；在体内，这可能代表了一种减少taf介导的对NK细胞功能的调节作用的控制机制。综上所述，这些发现表明来自结直肠癌患者肿瘤粘膜（TAF）的MSC可以下调结直肠癌肿瘤细胞的免疫细胞识别。这种免疫抑制可以通过CRC免疫治疗中使用的抗egfr抗体来缓解。
Mesenchymal stromal cells (MSC) present in the tumor microenvironment [usually named tumor-associated fibroblasts (TAF)] can exert immunosuppressive effects on T and natural killer (NK) lymphocytes, favoring tumor immune escape. We have analyzed this mechanism in colorectal carcinoma (CRC) and found that co-culture of NK cells with TAF can prevent the IL-2-mediated NKG2D upregulation. This leads to the impairment of NKG2D-mediated recognition of CRC cells, sparing the NK cell activation through DNAM1 or FcγRIIIA (CD16). In situ, TAF express detectable levels of epidermal growth factor receptor (EGFR); thus, the therapeutic anti-EGFR humanized antibody cetuximab can trigger the antibody-dependent cellular cytotoxicity of TAF, through the engagement of FcγRIIIA on NK cells. Importantly, in the tumor, we found a lymphoid infiltrate containing NKp46+CD3− NK cells, enriched in CD16+ cells. This population, sorted and cultured with IL-2, could be triggered via CD16 and via NKG2D. Of note, ex vivo NKp46+CD3− cells were able to kill autologous TAF; in vivo, this might represent a control mechanism to reduce TAF-mediated regulatory effect on NK cell function. Altogether, these findings suggest that MSC from the neoplastic mucosa (TAF) of CRC patients can downregulate the immune cell recognition of CRC tumor cells. This immunosuppression can be relieved by the anti-EGFR antibody used in CRC immunotherapy.
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影响因子：
4.4
作者：
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通讯作者：
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