CRM：消炎药帮T细胞“消灾”！最新科研揭示，COX1/2掌控剂可破解最致命乳腺癌中，巨噬细胞对T细胞功能的掌控
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<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">*仅供医学专业人士阅读参考</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">在奇点糕的印象里，<span style="color: black;">好似</span>有很<span style="color: black;">长期</span>没聊过什么“老药新用”的<span style="color: black;">科研</span>了，毕竟它们确实不如创新药宠儿们更受关注和追捧，但在研新药毕竟不是万能的，失败后还可能摔个万劫不复，而探索已有<span style="color: black;">药品</span>在癌症治疗中的新用法，<span style="color: black;">最少</span>不会有类似的<span style="color: black;">危害</span>，还可能意外挖到个宝呢。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">近期</span>，<span style="color: black;"><strong style="color: blue;">美国俄勒冈健康与科学大学（OHSU）<span style="color: black;">科研</span>者们在Cell Reports Medicine期刊<span style="color: black;">发布</span>的最新<span style="color: black;">科研</span>成果，就挖出了常用非甾体抗炎药（NSAIDs）COX1/2<span style="color: black;">控制</span>剂相当有前景的新用途：COX1/2<span style="color: black;">控制</span>剂能够<span style="color: black;">经过</span>解除巨噬细胞对T细胞功能的<span style="color: black;">控制</span>，与免疫<span style="color: black;">检测</span>点<span style="color: black;">控制</span>剂（ICIs）协同增效，用于最致命乳腺癌亚型——三阴性乳腺癌（TNBC）的治疗</strong></span>！</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">科研</span>者们借助高通量筛选（HTS）技术，在已获美国FDA<span style="color: black;">准许</span>的1400多种小分子<span style="color: black;">药品</span>中，筛选出了7个可有效解除巨噬细胞<span style="color: black;">控制</span>T细胞免疫功能的分子，其中竟然有4个是COX1/2<span style="color: black;">控制</span>剂，看来它们在增效免疫治疗方面的<span style="color: black;">潜能</span>确实不低，还是此前无人问津的宝藏呢。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://p3-sign.toutiaoimg.com/tos-cn-i-axegupay5k/69fdeda92b2d47f7a31d88d10e09e394~noop.image?_iz=58558&from=article.pc_detail&lk3s=953192f4&x-expires=1728087658&x-signature=yLeHTCOs90FLS1rY7HxRdWlL7j0%3D" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">论文核心机制总结</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">奇点糕就不多啰嗦巨噬细胞的<span style="color: black;">各样</span>免疫<span style="color: black;">控制</span><span style="color: black;">功效</span>机制了，直接快进到<span style="color: black;">这次</span><span style="color: black;">科研</span>的<span style="color: black;">重点</span>环节：<span style="color: black;">科研</span>者们<span style="color: black;">首要</span>将骨髓<span style="color: black;">源自</span>巨噬细胞（BMDMs）与脾脏<span style="color: black;">源自</span>的CD4+/CD8+T细胞共培养，确认BMDMs的免疫<span style="color: black;">控制</span>性，再用这个共培养阵列进行高通量筛选，<span style="color: black;">经过</span>T细胞荧光染色信号强度的改变，来判断<span style="color: black;">那些</span>已<span style="color: black;">获准</span>小分子<span style="color: black;">药品</span>能减轻BMDMs对T细胞的免疫<span style="color: black;">控制</span>。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">在以上初筛出的57个<span style="color: black;">药品</span>分子中，超过一半有着“炎症调节剂”（inflammatory modulators）的属性，<span style="color: black;">不外</span>57个候选分子还是太多了，于是<span style="color: black;">科研</span>者们又在共培养阵列中加入了PD-1/L1<span style="color: black;">控制</span>剂，<span style="color: black;">评定</span>候选分子们<span style="color: black;">是不是</span>能与现有免疫治疗协同增效，毕竟单兵作战的效果<span style="color: black;">常常</span>不如联合治疗，而这一步就卡掉了大<span style="color: black;">都数</span>候选分子，<span style="color: black;">仅有</span>8个分子达标<span style="color: black;">（T细胞信号<span style="color: black;">加强</span>≥1.3倍）</span>。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://p3-sign.toutiaoimg.com/tos-cn-i-tjoges91tu/dafbfb10e8d6c8409b5e05e8655810c8~noop.image?_iz=58558&from=article.pc_detail&lk3s=953192f4&x-expires=1728087658&x-signature=Ag2PtlHRkmty0%2FfqI2FkGH5zleE%3D" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">HTS筛选COX1/2<span style="color: black;">控制</span>剂的全过程</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">很巧的是，在最后入围的8个分子中，有6个仅与PD-L1<span style="color: black;">控制</span>剂协同增效<span style="color: black;">（1个仅与PD-1<span style="color: black;">控制</span>剂协同增效）</span>，且有4个是COX1/2<span style="color: black;">控制</span>剂，表现最好的是吲哚美辛，<span style="color: black;">科研</span>者们就<span style="color: black;">选取</span>了它用于下一步的TNBC模型小鼠实验，TNBC<span style="color: black;">始终</span>以治疗难度大、微环境免疫<span style="color: black;">控制</span>性强著<span style="color: black;">叫作</span>，且有<span style="color: black;">海量</span>髓系细胞浸润，其中COX2表达水平最高的正是巨噬细胞（F4/80+）。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">而小鼠实验的结果<span style="color: black;">能够</span>说好得不出所料，<strong style="color: blue;">吲哚美辛的单兵作战，就对两种<span style="color: black;">区别</span>TNBC细胞</strong><span style="color: black;">（4T1/EMT6）</span><strong style="color: blue;">形成的肿瘤分别展现了<span style="color: black;">显著</span>的<span style="color: black;">控制</span><span style="color: black;">功效</span></strong>，比PD-L1<span style="color: black;">控制</span>剂单独<span style="color: black;">运用</span><span style="color: black;">（仅可<span style="color: black;">控制</span>EMT6细胞成瘤）</span>表现都更好，<strong style="color: blue;">二者联合<span style="color: black;">运用</span>抑癌效果更强</strong>；<span style="color: black;">科研</span>者们用候选分子中的另一种COX1/2<span style="color: black;">控制</span>剂布洛芬替换掉吲哚美辛，取得的抑癌效果<span style="color: black;">亦</span>基本相同。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://p3-sign.toutiaoimg.com/tos-cn-i-tjoges91tu/7595f1c503bfe245729112cd198ebb95~noop.image?_iz=58558&from=article.pc_detail&lk3s=953192f4&x-expires=1728087658&x-signature=dzc0A7pwuGyDncfF1WQqdUb5Qi8%3D" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">吲哚美辛单兵作战或联合PD-L1<span style="color: black;">控制</span>剂<span style="color: black;">运用</span>均可有效<span style="color: black;">控制</span>TNBC，延长荷瘤小鼠<span style="color: black;">存活</span></span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">接下来的流式细胞术分析<span style="color: black;">亦</span>证实了HTS筛选<span style="color: black;">周期</span>的<span style="color: black;">发掘</span>，即COX1/2<span style="color: black;">控制</span>剂单药处理或联合PD-L1<span style="color: black;">控制</span>剂治疗，确实会直接改变TNBC微环境内的T细胞，<span style="color: black;">详细</span><span style="color: black;">来讲</span>是让CD8+效应T细胞<span style="color: black;">（表达颗粒酶B或T细胞因子TCF1）</span>的占比<span style="color: black;">明显</span><span style="color: black;">提升</span>，而巨噬细胞的<span style="color: black;">重点</span>改变则是共刺激分子CD86，以及MHC-II类分子的表达<span style="color: black;">明显</span>上调。但<span style="color: black;">一样</span>以巨噬细胞为<span style="color: black;">重点</span><span style="color: black;">功效</span>对象的在研新药CSF1R单抗，并不会对COX1/2<span style="color: black;">控制</span>剂的抑癌<span style="color: black;">功效</span>产生<span style="color: black;">显著</span>影响。</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://p3-sign.toutiaoimg.com/tos-cn-i-tjoges91tu/6cb6c824fec101c61a9bb5fabfec8f87~noop.image?_iz=58558&from=article.pc_detail&lk3s=953192f4&x-expires=1728087658&x-signature=C%2B6poGKsu26c8CF5fZRYH6pMuw0%3D" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">COX1/2<span style="color: black;">控制</span>剂的抑癌<span style="color: black;">功效</span>是CD8+效应T细胞依赖性的</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">说到这儿，奇点糕还真有一种“殊途同归”的感觉，前几天刚聊过的另一项<span style="color: black;">科研</span>里，我国学者不<span style="color: black;">便是</span>用COX1/2<span style="color: black;">控制</span>剂来阻断前列腺素E2（PGE2）生成，不让<span style="color: black;">身体</span>巨噬细胞沦为促癌<span style="color: black;">走狗</span>么？只能说两项成功的<span style="color: black;">科研</span>重合到<span style="color: black;">一块</span>了，赶紧快进到临床<span style="color: black;">科研</span>带来<span style="color: black;">更加多</span>的成功吧<span style="color: black;">（请勿<span style="color: black;">自动</span><span style="color: black;">弥补</span>后续台词）</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;">------</p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><strong style="color: blue;">奇点糕近期推出了《2024ASCO年会深度盘点》课程，为<span style="color: black;">大众</span>系统盘点了2024ASCO年会上实体瘤<span style="color: black;">行业</span>的重磅<span style="color: black;">发展</span>，让您在100分钟内<span style="color: black;">快速</span>深入把握前沿。</strong></span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><strong style="color: blue;">长按识别下图中的二维码<span style="color: black;">就可</span>购买，购买后您<span style="color: black;">能够</span>在「奇点网小程序」收听，或下载奇点网「医学奇点」苹果客户端收听。</strong></span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;"><strong style="color: blue;"><span style="color: black;">倘若</span>遇到任何技术问题，<span style="color: black;">大众</span><span style="color: black;">能够</span>戳<span style="color: black;">咱们</span>下图中的客服小伙伴来<span style="color: black;">处理</span>~~</strong></span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://p3-sign.toutiaoimg.com/tos-cn-i-tjoges91tu/7af0d675bb1624135707e778bde53f22~noop.image?_iz=58558&from=article.pc_detail&lk3s=953192f4&x-expires=1728087658&x-signature=Y%2Fj6lPieFxHW%2FQlEfu%2F%2BjRfQJlg%3D" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://p3-sign.toutiaoimg.com/tos-cn-i-tjoges91tu/87795ee643cbf3d1e759f980991acca9~noop.image?_iz=58558&from=article.pc_detail&lk3s=953192f4&x-expires=1728087658&x-signature=9%2BHGYPtZbA%2BBVT9qiUvXqIeKGDA%3D" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">参考文献：</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">Kumar S, Tailor D, Dheeraj A, et al. Uncovering therapeutic targets for macrophage-mediated T cell suppression and PD-L1 therapy sensitization. Cell Reports Medicine, 2024.</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">DeNardo D G, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nature Reviews Immunology, 2019, 19(6): 369-382.</span></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><img src="https://p26-sign.toutiaoimg.com/tos-cn-i-tjoges91tu/f01a797dd54df5edf4441f370e2e6152~noop.image?_iz=58558&from=article.pc_detail&lk3s=953192f4&x-expires=1728087658&x-signature=MfTZsudWEdyPVcIjCxidR5uZXg4%3D" style="width: 50%; margin-bottom: 20px;"></p>
<p style="font-size: 16px; color: black; line-height: 40px; text-align: left; margin-bottom: 15px;"><span style="color: black;">本文作者丨谭硕</span></p>
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