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我国发现新肿瘤免疫抑制受体，可产生广谱抗肿瘤效果—新闻—科学网
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font: 12px 宋体; float: right"> 选择字号：<span onclick="showsize(12)" style="background-color: #587c19; color: #fff; font-size: 12px; cursor: pointer">小</span> <span onclick="showsize(14)" style="background-color: #587c19; color: #fff; font-size: 12px; cursor: pointer">中</span> <span onclick="showsize(16)" style="background-color: #587c19; color: #fff; font-size: 12px; cursor: pointer"> 大</span> </div> </td> </tr> <tr> <td align="center"> <div id="content1" style=" padding:15px; text-align: left; line-height: 24px; word-wrap: break-word;word-break:break-all" class="f14"> <table width="100%" border="0" cellspacing="0" cellpadding="0"> <tr> <td height="20"> </td> </tr> <tr> <td align="center" valign="middle" class="style1" style="font-size: 13px; color: #333333; font-family: 宋体; line-height: 20px"> <b></b></td> </tr> <tr> <td align="center" class="style1" style="font-size: 22px; color: #587c19; font-family: 黑体; line-height: 30px"> 我国发现新肿瘤免疫抑制受体，可产生广谱抗肿瘤效果</td> </tr> <tr> <td align="center" valign="middle" class="style1" style="font-size: 13px; color: #333333; font-family: 宋体; line-height: 20px"> <b></b></td> </tr> </table> <p > </p><p style=";; margin: 0px 0px 26px; text-align: justify; word-break: break-all;">上海专家在《自然》（Nature）杂志最新发表的研究显示，CD300ld靶点有望成为肿瘤免疫治疗新的理想靶点。</p> <p style="text-align: center;"><span style="display: inline-block; max-width: 100%;"><img alt="" src="https://rmtzx.sciencenet.cn//kxwsprint/64fa67b6e4b0e807c6f8ccd9.jpeg" style="vertical-align: middle; border-style: none; display: block; margin-right: auto; margin-left: auto; color: rgb(51, 51, 51); font-family: MicrosoftYaHei; letter-spacing: 0.5px; white-space: normal; background-color: rgb(248, 249, 249); width: 100%; height: auto !important;" _src="https://imagecloud.thepaper.cn/thepaper/image/269/111/548.PNG" data-id="44932" data-wenge-id="44932" data-mce-src="https://rmtzx.sciencenet.cn//kxwsprint/64fa67b6e4b0e807c6f8ccd9.jpeg" id="img-null"></span></p> <p style=";; margin: 0px 0px 26px; text-align: center; word-break: break-all;">论文截图。本文图片均为 复旦大学附属儿科医院 供图</p> <p style=";; margin: 0px 0px 26px; text-align: justify; word-break: break-all;">9月7日，澎湃新闻记者从复旦大学附属儿科医院获悉，2023年9月6日，复旦大学罗敏/卢智刚/高海团队和中国科学院分子细胞科学卓越创新中心赵允团队合作在Nature杂志在线发表题为CD300ld on neutrophils is required for tumour-driven immune suppression的研究文章。该研究发现一个全新的、功能高度保守的肿瘤免疫抑制受体CD300ld。CD300ld在PMN-MDSCs上特异性高表达，是调控PMN-MDSCs募集及免疫抑制功能的关键受体。靶向CD300ld能够通过抑制PMN-MDSCs的募集和功能，重塑肿瘤免疫微环境，从而产生广谱抗肿瘤效果。CD300ld靶点显示出很好的安全性、保守性，抗肿瘤有效性、及与PD1靶点的协同性，有望成为肿瘤免疫治疗新的理想靶点。</p> <p style=";; margin: 0px 0px 26px; text-align: justify; word-break: break-all;">专家表示，以PD-1/PD-L1/CTLA-4等分子为代表的免疫检查点阻断（ICB）疗法，是近年来在肿瘤治疗领域中的革命性进展。然而，现有ICB在不同肿瘤病人当中的效果差异很大，相当比例的患者无应答，长期获益比例更低。肿瘤免疫微环境含有大量抑制免疫的髓系细胞群体，在肿瘤发展和治疗耐受中发挥关键作用，是现有免疫治疗的严重阻碍。</p> <p style=";; margin: 0px 0px 26px; text-align: justify; word-break: break-all;">病理性激活的中性粒细胞（也被称为多形核髓系来源的抑制细胞：Polymorphonuclear myeloid derived suppressor cells, PMN-MDSCs）是免疫抑制微环境的重要组成细胞。与正常的中性粒细胞不同，PMN-MDSCs具有强烈抑制淋巴细胞杀伤的作用，通过多种途径参与肿瘤进展。寻找针对PMN-MDSCs的特异性靶点来调控肿瘤免疫微环境是当前免疫治疗的焦点和挑战。</p> <p style="text-align: center;"><img alt="" src="https://rmtzx.sciencenet.cn//kxwsprint/64fa67b6e4b0e807c6f8ccdb.jpeg" style="vertical-align: middle; border-style: none; display: block; margin-right: auto; margin-left: auto; color: rgb(51, 51, 51); font-family: MicrosoftYaHei; letter-spacing: 0.5px; white-space: normal; background-color: rgb(248, 249, 249); width: 618px; height: auto !important;" _src="https://imagecloud.thepaper.cn/thepaper/image/269/111/547.JPG" data-id="44933" data-wenge-id="44933" data-mce-src="https://rmtzx.sciencenet.cn//kxwsprint/64fa67b6e4b0e807c6f8ccdb.jpeg" id="img-null"></p> <p style=";; margin: 0px 0px 26px; text-align: center; word-break: break-all;">研究图示。</p> <p style=";; margin: 0px 0px 26px; text-align: justify; word-break: break-all;">聚焦这一科学问题，此次研究人员首先以髓系细胞偏向表达的系列膜蛋白为对象，利用小鼠肿瘤模型进行CRISPR-Cas9体内筛选，发现缺失CD300ld的免疫细胞在肿瘤中缺失最为显著，提示表达CD300ld的细胞可能促进肿瘤发展。CD300ld在中性粒细胞中特异性高表达、并在荷瘤之后表达显著上调。随后研究者构建CD300ld敲除小鼠，证实CD300ld缺失显著抑制多种继发性及原发性肿瘤模型的发展；同时CD300ld敲除对小鼠的正常发育以及免疫系统发育无显著影响。通过骨髓移植、构建多种条件性敲除小鼠、以及清除体内PMN-MDSCs等多种手段，结果证实CD300ld通过PMN-MDSCs调控肿瘤发展。因此，CD300ld作为中性粒细胞/PMN-MDSCs表面标志物，是PMN-MDSCs促进肿瘤发展的关键功能受体。</p> <p style=";; margin: 0px 0px 26px; text-align: justify; word-break: break-all;">为进一步研究人CD300ld的同功性，研究者分析了TCGA数据库以及多例不同类型肿瘤的病人样本。结果显示，CD300ld也在人中性粒细胞/PMN-MDSCs上特异性高表达；同时在多种癌种中，CD300LD的表达显著高于癌旁以及正常组织，并与中性粒细胞的浸润以及病人预后显著相关。研究者随后构建CD300LD人源化小鼠，进一步证明人鼠CD300ld功能同源，竞争性抑制人CD300LD也呈现出显著抗肿瘤效果。</p> <p style=";; margin: 0px 0px 26px; text-align: justify; word-break: break-all;">综上所述，该项研究发现了PMN-MDSCs表面的关键功能受体CD300ld，在肿瘤免疫抑制中发挥重要作用。CD300ld通过STAT3-S100A8/A9轴同时调控PMN-MDSCs的募集及其T细胞抑制功能，从而促进免疫抑制微环境的建立和肿瘤的进展。阻断CD300ld通过减少PMN-MDSCs的募集并降低其免疫抑制功能，重塑免疫微环境由免疫抑制状态转为活化状态，从而产生广谱抗肿瘤效果。</p> <p style=";; margin: 0px 0px 26px; text-align: justify; word-break: break-all;">中国科学院分子细胞科学卓越创新中心博士后王超雄、复旦大学附属儿科医院/生物医学研究院博士后郑曦晨、复旦大学生物医学研究院/附属第五人民医院研究助理张金兰为本文共同第一作者。复旦大学附属儿科医院/生物医学研究院罗敏研究员、中国科学院分子细胞科学卓越创新中心赵允研究员、复旦大学生物医学研究院/附属第五人民医院卢智刚研究员、复旦大学生物医学研究院/附属徐汇中心医院高海研究员为该论文共同通讯作者。</p> <p class="lastPadding" style=";; margin: 0px 0px 26px; text-align: justify; word-break: break-all;">（原标题：上海专家发现新的肿瘤免疫抑制受体，可产生广谱抗肿瘤效果）</p><div> </div><div style="text-indent:2em;color: #587c19;font-size:13px; 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