Smad4 Deficiency Promotes Pancreatic Cancer Immunogenicity by Activating the Cancer-Autonomous DNA-Sensing Signaling Axis.
Smad4 Deficiency Promotes Pancreatic Cancer Immunogenicity by Activating the Cancer-Autonomous DNA-Sensing Signaling Axis.
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Smad4 缺陷通过激活癌症自主 DNA 传感信号轴促进胰腺癌免疫原性
DOI：
10.1002/advs.202103029
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发表时间：
2022-03
期刊：
影响因子：
--
通讯作者：
Xia X
中科院分区：
文献类型：
--
作者：
Xiong W;He W;Wang T;He S;Xu F;Wang Z;Wang X;Guo H;Ling J;Zhang H;Liu Y;Xing K;Li M;Zhang H;Li J;Niu N;Xue J;Zhan Q;Liu ZX;Bei JX;Huang P;Liu J;Xia L;Xia X
Smad 4是转化生长因子β信号传导的关键介质，在20%的胰腺导管腺癌（PDAC）癌症中突变或缺失，并显著影响癌症的发展。然而，Smad 4缺失对PDAC免疫原性和肿瘤免疫微环境的影响尚不清楚。在这里，Smad 4在抑制小鼠PDAC肿瘤免疫原性中的令人惊讶的功能被鉴定。尽管肿瘤细胞中的Smad 4缺失增强了体外增殖，但在免疫活性C57 BL/6（B6）小鼠中，Smad 4缺陷型PDAC肿瘤的体内生长受到显著抑制，但在免疫缺陷小鼠或CD 8+细胞缺失的B6小鼠中则没有。从机制上讲，Smad 4缺陷通过促进自发DNA损伤和刺激STING介导的I型干扰素信号传导显著增加肿瘤细胞免疫原性，这有助于激活1型常规树突状细胞（cDC 1）和随后的CD 8 + T细胞用于肿瘤控制。此外，当Sting共缺失时，或者当细胞植入干扰素α受体缺陷小鼠或cDC 1缺陷小鼠时，B6小鼠中Smad 4缺陷PDAC细胞的肿瘤生长延迟在很大程度上逆转。因此，Smad 4缺陷通过诱导肿瘤内源性DNA损伤引发的I型干扰素信号传导促进PDAC免疫原性。作者的研究结果确定，通常失活的肿瘤抑制因子Smad 4是通过激活癌症自主DNA传感信号传导来调节胰腺导管腺癌肿瘤免疫原性的关键调节因子，并表明Smad 4表达作为生物标志物在开发未来有效的PDAC免疫疗法中的潜在作用。
Smad4, a key mediator of the transforming growth factor‐β signaling, is mutated or deleted in 20% of pancreatic ductal adenocarcinoma (PDAC) cancers and significantly affects cancer development. However, the effect of Smad4 loss on the immunogenicity and tumor immune microenvironment of PDAC is still unclear. Here, a surprising function of Smad4 in suppressing mouse PDAC tumor immunogenicity is identified. Although Smad4 deletion in tumor cells enhances proliferation in vitro, the in vivo growth of Smad4‐deficient PDAC tumor is significantly inhibited on immunocompetent C57BL/6 (B6) mice, but not on immunodeficient mice or CD8+ cell‐depleted B6 mice. Mechanistically, Smad4 deficiency significantly increases tumor cell immunogenicity by promoting spontaneous DNA damage and stimulating STING‐mediated type I interferon signaling,which contributes to the activation of type 1 conventional dendritic cells (cDC1) and subsequent CD8+ T cells for tumor control. Furthermore, retarded tumor growth of Smad4‐deficient PDAC cells on B6 mice is largely reversed when Sting is codeleted, or when the cells are implanted into interferon‐alpha receptor‐deficientmice or cDC1‐deficientmice. Accordingly, Smad4 deficiency promotes PDAC immunogenicity by inducing tumor‐intrinsic DNA damage‐elicited type I interferon signaling. The author's findings establish that the commonly inactivated tumor suppressor Smad4 is a critical regulator of pancreatic ductal adenocarcinoma tumor immunogenicity by activating cancer‐autonomous DNA sensing signaling, and suggest a potential role of Smad4 expression as a biomarker in developing future effective immunotherapy for PDACs.
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DOI：
10.1084/jem.20101159
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Fuertes MB;Kacha AK;Kline J;Woo SR;Kranz DM;Murphy KM;Gajewski TF
通讯作者：
Gajewski TF
影响因子：
64.8
作者：
Li S;Liu M;Do MH;Chou C;Stamatiades EG;Nixon BG;Shi W;Zhang X;Li P;Gao S;Capistrano KJ;Xu H;Cheung NV;Li MO
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Li MO
DOI：
10.1084/jem.20101158
发表时间：
2011-09-26
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Diamond MS;Kinder M;Matsushita H;Mashayekhi M;Dunn GP;Archambault JM;Lee H;Arthur CD;White JM;Kalinke U;Murphy KM;Schreiber RD
通讯作者：
Schreiber RD
影响因子：
28.2
作者：
Li J;Yuan S;Norgard RJ;Yan F;Sun YH;Kim IK;Merrell AJ;Sela Y;Jiang Y;Bhanu NV;Garcia BA;Vonderheide RH;Blanco A;Stanger BZ
通讯作者：
Stanger BZ
影响因子：
50.3
作者：
Ahn J;Xia T;Rabasa Capote A;Betancourt D;Barber GN
通讯作者：
Barber GN