在過去的十年里，免疫檢查點封閉抗體的使用徹底改變了癌癥治療。CTLA-4和PD-1阻斷抗體是轉移性黑色素瘤患者最常用的免疫療法之一，但許多患者使用后仍無反應，復發(fā)很常見。CTLA-4治療僅在大約20%患者中有效。最近的研究結果表明，腸道菌群的組成與CTLA-4和PD-1抗體的抗腫瘤功效有關。
眾所周知，腸道中的一些共生細菌群產生的代謝物在免疫反應的調節(jié)中起著關鍵作用。這些代謝物包括短鏈脂肪酸?(short-chain fatty acids ,SCFAs)，主要是乙酸酯(C2)、丙酸酯(C3)和丁酸酯(C4)?？紤]到這一點，法國Villejuif的Gustave Roussy癌癥研究所的Nathalie Chaput博士的研究小組假設CTLA-4抗體的抗腫瘤效果可能受到體內微生物產生的短鏈脂肪酸的影響。
為了驗證這一假設，將丁酸鹽通過飲用水給予荷瘤小鼠。這些小鼠還接受了CTLA-4抗體或其同種型對照的i.p .注射。令人驚訝的是，在三種不同的腫瘤模型(CT26、MC38和MCA101)中，添加丁酸鹽消除了CTLA-4的抗腫瘤作用。進一步研究，作者發(fā)現(xiàn)丁酸鹽阻斷了CTLA-4抗體誘導的樹突細胞成熟，這限制了樹突細胞刺激T細胞的能力，從而限制了抗腫瘤免疫能力。該小組發(fā)現(xiàn)，用ipilimumab(anti?CTLA-4)治療者的血液中丁酸鹽水平高的黑色素瘤患者減少了記憶T細胞的積累。
以上研究成果發(fā)布在Nature?Communications文獻?” Systemic short chain fatty acids limit antitumor effect of CTLA-4 blockade in hosts with cancer”?中，該研究小組使用了BioXCell的InVivoPlus anti-mouse CLTA-4(Clone: 9D9)抗體,?揭示了微生物產生的短鏈脂肪酸對CTLA-4抗體抗腫瘤的效果抑制。
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摘要：Gut microbiota composition influences the clinical benefit of immune checkpoints in patients with advanced cancer but mechanisms underlying this relationship remain unclear. Molecular mechanism whereby gut microbiota influences immune responses is mainly assigned to gut microbial metabolites. Short-chain fatty acids (SCFA) are produced in large amounts in the colon through bacterial fermentation of dietary fiber. We evaluate in mice and in patients treated with anti-CTLA-4 blocking mAbs whether SCFA levels is related to clinical outcome. ?High blood butyrate and propionate levels are associated with resistance to CTLA-4 blockade and higher proportion of Treg cells. In mice, butyrate restrains anti-CTLA-4-induced upregulation of CD80/CD86 on dendritic cells and ICOS on T cells, accumulation of tumor-specific T cells and memory T cells. In patients, high blood butyrate levels moderate ipilimumab-induced accumulation of memory and ICOS + CD4 + T cells and IL-2 impregnation. Altogether, these results suggest that SCFA limits anti-CTLA-4 activity.
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文章鏈接：https://www.nature.com/articles/s41467-020-16079-x
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訂購詳情：
產品名稱 | 貨號 | 規(guī)格 |
InVivoMAb anti-mouse CTLA-4 (CD152) | BE0164 | 1/5/25/50/100mg |
InVivoPlus anti-mouse CTLA-4 (CD152) | BP0164 | 1/5/25/50/100mg |
詳情請咨詢?BioXcell?中國授權代理-欣博盛生物科技
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