Improving function of cytotoxic T-lymphocytes by transforming growth factor-β inhibitor in oral squamous cell carcinoma.
Improving function of cytotoxic T-lymphocytes by transforming growth factor-β inhibitor in oral squamous cell carcinoma.
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DOI：
10.1111/cas.15081
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发表时间：
2021-10
期刊：
影响因子：
5.7
通讯作者：
Nagao T
中科院分区：
文献类型：
--
作者：
Kondo Y;Suzuki S;Takahara T;Ono S;Goto M;Miyabe S;Sugita Y;Ogawa T;Ito H;Satou A;Tsuzuki T;Yoshikawa K;Ueda R;Nagao T
免疫检查点疗法的免疫疗法最近被用于治疗口腔鳞状细胞癌（OSCC）。然而，由于反应率有限，目前的免疫疗法有望得到改善。转化生长因子-β（TGF-β）通过诱导调节性T细胞（TlC）和癌症相关成纤维细胞的产生并抑制细胞毒性T淋巴细胞（CTL）和自然杀伤细胞的功能，产生免疫抑制性肿瘤微环境（TME）。TGF-β可能是开发新型癌症免疫疗法的重要靶点。在这项研究中，我们研究了TGF-β对CTL功能的抑制作用，在体外使用OSCC细胞系及其特异性CTL。采用原位杂交和免疫组化方法检测25例口腔鳞癌组织中TGFB 1 mRNA的表达和T细胞浸润情况。我们发现，TGF-β在体外抑制抗原特异性CTL在致敏和效应阶段的功能。此外，TGF-β抑制剂有效地恢复了CTL功能，并且TGFB 1 mRNA主要在肿瘤浸润前沿表达。有趣的是，我们发现TGFB 1 mRNA表达与CD 8 + T细胞/Treg比率之间以及TGFB 1 mRNA表达与CD 8 + T细胞中Ki-67表达之间存在显著负相关性，表明TGF-β也抑制了原位CTL的功能。我们的研究结果表明，TGF-β功能的调节使免疫抑制性TME恢复到活性状态，对于开发新的免疫抑制策略（例如免疫检查点抑制剂和TGF-β抑制剂的组合）对于OSCC非常重要。我们发现，TGF-β在体外抑制抗原特异性CTL在致敏和效应阶段的功能。并且，我们发现TGFB 1 mRNA表达与CD 8 + T细胞/Treg比率之间存在显著负相关性。TGF-β的抑制通过与免疫检查点抑制剂不同的机制使免疫抑制性TME恢复到活性状态，这表明两者的组合可能导致OSCC的新治疗策略。
Immunotherapy with immune‐checkpoint therapy has recently been used to treat oral squamous cell carcinomas (OSCCs). However, improvements in current immunotherapy are expected because response rates are limited. Transforming growth factor‐β (TGF‐β) creates an immunosuppressive tumor microenvironment (TME) by inducing the production of regulatory T‐cells (Tregs) and cancer‐associated fibroblasts and inhibiting the function of cytotoxic T‐lymphocytes (CTLs) and natural killer cells. TGF‐β may be an important target in the development of novel cancer immunotherapies. In this study, we investigated the suppressive effect of TGF‐β on CTL function in vitro using OSCC cell lines and their specific CTLs. Moreover, TGFB1 mRNA expression and T‐cell infiltration in 25 OSCC tissues were examined by in situ hybridization and multifluorescence immunohistochemistry. We found that TGF‐β suppressed the function of antigen‐specific CTLs in the priming and effector phases in vitro. Additionally, TGF‐β inhibitor effectively restored the CTL function, and TGFB1 mRNA was primarily expressed in the tumor invasive front. Interestingly, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T‐cell/Treg ratio and between TGFB1 mRNA expression and the Ki‐67 expression in CD8+ T‐cells, indicating that TGF‐β also suppressed the function of CTLs in situ. Our findings suggest that the regulation of TGF‐β function restores the immunosuppressive TME to active status and is important for developing new immunotherapeutic strategies, such as a combination of immune‐checkpoint inhibitors and TGF‐β inhibitors, for OSCCs. We found that, TGF‐β suppressed the function of antigen‐specific CTLs in the priming and effector phases in vitro. And, we found a significant negative correlation between TGFB1 mRNA expression and the CD8+ T‐cell/Treg ratio. Inhibition of TGF‐β restores the immunosuppressive TME to active status by a mechanism different from that of immune‐checkpoint inhibitors, suggesting that the combination of both may lead to a new therapeutic strategy for OSCCs.
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影响因子：
39.3
作者：
Liu S;Ren J;Ten Dijke P
通讯作者：
Ten Dijke P
DOI：
10.1042/cs20110434
发表时间：
2012-05-01
期刊：
Clinical science (London, England : 1979)
影响因子：
--
作者：
Chen MF;Wang WH;Lin PY;Lee KD;Chen WC
通讯作者：
Chen WC
影响因子：
11.2
作者：
Lu, SL;Reh, D;Wang, XJ
通讯作者：
Wang, XJ
影响因子：
64.5
作者：
Hugo W;Zaretsky JM;Sun L;Song C;Moreno BH;Hu-Lieskovan S;Berent-Maoz B;Pang J;Chmielowski B;Cherry G;Seja E;Lomeli S;Kong X;Kelley MC;Sosman JA;Johnson DB;Ribas A;Lo RS
通讯作者：
Lo RS
影响因子：
64.8
作者：
Mariathasan S;Turley SJ;Nickles D;Castiglioni A;Yuen K;Wang Y;Kadel EE III;Koeppen H;Astarita JL;Cubas R;Jhunjhunwala S;Banchereau R;Yang Y;Guan Y;Chalouni C;Ziai J;Şenbabaoğlu Y;Santoro S;Sheinson D;Hung J;Giltnane JM;Pierce AA;Mesh K;Lianoglou S;Riegler J;Carano RAD;Eriksson P;Höglund M;Somarriba L;Halligan DL;van der Heijden MS;Loriot Y;Rosenberg JE;Fong L;Mellman I;Chen DS;Green M;Derleth C;Fine GD;Hegde PS;Bourgon R;Powles T
通讯作者：
Powles T