β-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer.
β-Catenin Drives Butyrophilin-like Molecule Loss and γδ T-cell Exclusion in Colon Cancer.
复制标题
β-Catenin驱动结肠癌中亲丁酸蛋白样分子丢失和γδ t细胞排斥
DOI：
10.1158/2326-6066.cir-22-0644
复制
发表时间：
2023-08-03
影响因子：
10.1
通讯作者：
Coffelt, Seth B.
中科院分区：
文献类型：
--
作者：
Suzuki, Toshiyasu;Kilbey, Anna;Casa-Rodriguez, Nuria;Lawlor, Amy;Georgakopoulou, Anastasia;Hayman, Hannah;Swe, Kyi Lai Yin;Nordin, Anna;Cantu, Claudio;Vantourout, Pierre;Ridgway, Rachel A.;Byrne, Ryan M.;Chen, Lei;Verzi, Michael P.;Gay, David M.;Vazquez, Ester Gil;Belnoue-Davis, Hayley L.;Gilroy, Kathryn;Kostner, Anne Helene;Kersten, Christian;Thuwajit, Chanitra;Andersen, Ditte K.;Wiesheu, Robert;Jandke, Anett;Blyth, Karen;Roseweir, Antonia K.;Leedham, Simon J.;Dunne, Philip D.;Edwards, Joanne;Hayday, Adrian;Sansom, Owen J.;Coffelt, Seth B.
γδ T细胞具有固有的抗癌活性，但肿瘤如何破坏这些细胞的免疫监视尚不清楚。作者确定了WNT驱动的免疫逃逸对抗肿瘤组织驻留γδ T细胞的机制，该机制对结肠癌具有特异性。表达γδ T细胞受体（γδTCR）的上皮内淋巴细胞（IEL）在结肠癌的消除中起关键作用。然而，进展中的癌细胞逃避这些先天性T细胞免疫监视的确切机制尚不清楚。在这里，我们研究了肠道组织中Apc肿瘤抑制因子的缺失如何使新生癌细胞逃脱细胞毒性γδ IEL的免疫监视。与健康的肠或结肠组织相比，我们发现γδ IEL在小鼠和人肿瘤的微环境中基本上不存在，并且可以通过直接γδTCR相互作用来关键调节γδIEL的亲酪蛋白样（BTNL）分子在肿瘤中也下调。然后，我们证明了通过Apc的丧失而激活的β-连环蛋白快速抑制编码HNF 4A和HNF 4G转录因子的mRNA的表达，从而阻止它们与Btnl基因的启动子区域结合。在共培养试验中，癌细胞中BTNL 1和BTNL 6的再表达增加了γδIEL的存活和活化，但未能增强它们的体外癌症杀伤能力或它们向原位肿瘤的募集。然而，在Apc缺陷或突变的β-连环蛋白小鼠模型中，通过基因缺失Bcl 9/Bcl 9 L抑制β-连环蛋白信号传导恢复了Hnf 4a、Hnf 4g和Btnl基因表达和γδ T细胞浸润到肿瘤中。这些观察结果强调了WNT驱动的结肠癌细胞特异性的免疫逃避机制，其破坏γδIEL免疫监视并促进癌症进展。
γδ T cells harbor inherent anticancer activity, but how tumors subvert immunosurveillance by these cells is unclear. The authors identify a mechanism of WNT-driven immune escape from antitumor tissue-resident γδ T cells that is specific to colon cancer. Intraepithelial lymphocytes (IEL) expressing γδ T-cell receptors (γδTCR) play key roles in elimination of colon cancer. However, the precise mechanisms by which progressing cancer cells evade immunosurveillance by these innate T cells are unknown. Here, we investigated how loss of the Apc tumor suppressor in gut tissue could enable nascent cancer cells to escape immunosurveillance by cytotoxic γδIELs. In contrast with healthy intestinal or colonic tissue, we found that γδIELs were largely absent from the microenvironment of both mouse and human tumors, and that butyrophilin-like (BTNL) molecules, which can critically regulate γδIEL through direct γδTCR interactions, were also downregulated in tumors. We then demonstrated that β-catenin activation through loss of Apc rapidly suppressed expression of the mRNA encoding the HNF4A and HNF4G transcription factors, preventing their binding to promoter regions of Btnl genes. Reexpression of BTNL1 and BTNL6 in cancer cells increased γδIEL survival and activation in coculture assays but failed to augment their cancer-killing ability in vitro or their recruitment to orthotopic tumors. However, inhibition of β-catenin signaling via genetic deletion of Bcl9/Bcl9L in either Apc-deficient or mutant β-catenin mouse models restored Hnf4a, Hnf4g, and Btnl gene expression and γδ T-cell infiltration into tumors. These observations highlight an immune-evasion mechanism specific to WNT-driven colon cancer cells that disrupts γδIEL immunosurveillance and furthers cancer progression.
影响因子：
16.6
作者：
Pickering KA;Gilroy K;Cassidy JW;Fey SK;Najumudeen AK;Zeiger LB;Vincent DF;Gay DM;Johansson J;Fordham RP;Miller B;Clark W;Hedley A;Unal EB;Kiel C;McGhee E;Machesky LM;Nixon C;Johnsson AE;Bain M;Strathdee D;van Hoof SR;Medema JP;Anderson KI;Brachmann SM;Stucke VM;Malliri A;Drysdale M;Turner M;Serrano L;Myant K;Campbell AD;Sansom OJ
通讯作者：
Sansom OJ