DNASE1L3 enhances antitumor immunity and suppresses tumor progression in colon cancer.
DNASE1L3 enhances antitumor immunity and suppresses tumor progression in colon cancer.
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DOI：
10.1172/jci.insight.168161
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发表时间：
2023-09-08
期刊：
影响因子：
8
通讯作者：
Li, Leping
中科院分区：
文献类型：
--
作者：
Li, Wenling;Nakano, Hideki;Fan, Wei;Li, Yuanyuan;Sil, Payel;Nakano, Keiko;Zhao, Fei;Karmaus, Peer W.;Grimm, Sara A.;Shi, Min;Xu, Xin;Mizuta, Ryushin;Kitamura, Daisuke;Wan, Yisong;Fessler, Michael B.;Cook, Donald N.;Shats, Igor;Li, Xiaoling;Li, Leping
DNASE1L3是一种在DC中高度表达的酶，在调节自身DNA和染色质的自身免疫反应中具有重要的功能。DNASE1L3的缺乏导致人类和小鼠中自身免疫性疾病的发展。然而，尽管DNASE1L3和免疫之间的因果关系已经确立，但关于DNASE1L3参与调节抗肿瘤免疫，现代抗肿瘤免疫治疗的基础，却知之甚少。在这项研究中，我们确定DNASE1L3作为一个潜在的新的抗肿瘤免疫调节剂和结肠癌的肿瘤抑制因子。在人类中，DNASE1L3在肿瘤浸润性DC中下调，这种下调与许多癌症类型中患者预后不良和肿瘤免疫细胞浸润减少有关。在小鼠中，肿瘤微环境中的Dnase1l3缺陷增强了几种结肠癌模型中的肿瘤形成和生长。值得注意的是，在Dnase113缺陷小鼠中增加的肿瘤形成和生长与抗肿瘤免疫受损相关，如细胞毒性T细胞和独特的DC亚群的大幅减少所证明的。因此，Dnase113缺陷的DC在体外直接调节细胞毒性T细胞。据我们所知，我们的研究揭示了DNASE1L3和抗肿瘤免疫之间以前未知的联系，并进一步表明，恢复DNASE1L3活性可能代表一种潜在的抗癌治疗方法。
DNASE1L3, an enzyme highly expressed in DCs, is functionally important for regulating autoimmune responses to self-DNA and chromatin. Deficiency of DNASE1L3 leads to development of autoimmune diseases in both humans and mice. However, despite the well-established causal relationship between DNASE1L3 and immunity, little is known about the involvement of DNASE1L3 in regulation of antitumor immunity, the foundation of modern antitumor immunotherapy. In this study, we identify DNASE1L3 as a potentially new regulator of antitumor immunity and a tumor suppressor in colon cancer. In humans, DNASE1L3 is downregulated in tumor-infiltrating DCs, and this downregulation is associated with poor patient prognosis and reduced tumor immune cell infiltration in many cancer types. In mice, Dnase1l3 deficiency in the tumor microenvironment enhances tumor formation and growth in several colon cancer models. Notably, the increased tumor formation and growth in Dnase1l3-deficient mice are associated with impaired antitumor immunity, as evidenced by a substantial reduction of cytotoxic T cells and a unique subset of DCs. Consistently, Dnase1l3-deficient DCs directly modulate cytotoxic T cells in vitro. To our knowledge, our study unveils a previously unknown link between DNASE1L3 and antitumor immunity and further suggests that restoration of DNASE1L3 activity may represent a potential therapeutic approach for anticancer therapy.
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影响因子：
30.8
作者：
Napirei, M;Karsunky, H;Möröy, T
通讯作者：
Möröy, T
影响因子：
4.1
作者：
Napirei, M;Wulf, S;Kloeckl, T
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影响因子：
56.9
作者：
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通讯作者：
DOVE, WF
影响因子：
7
作者：
Mittra I;Samant U;Sharma S;Raghuram GV;Saha T;Tidke P;Pancholi N;Gupta D;Prasannan P;Gaikwad A;Gardi N;Chaubal R;Upadhyay P;Pal K;Rane B;Shaikh A;Salunkhe S;Dutt S;Mishra PK;Khare NK;Nair NK;Dutt A
通讯作者：
Dutt A
DOI：
10.1084/jem.20201138
发表时间：
2021-05-03
期刊：
The Journal of experimental medicine
影响因子：
--
作者：
Hartl J;Serpas L;Wang Y;Rashidfarrokhi A;Perez OA;Sally B;Sisirak V;Soni C;Khodadadi-Jamayran A;Tsirigos A;Caiello I;Bracaglia C;Volpi S;Ghiggeri GM;Chida AS;Sanz I;Kim MY;Belmont HM;Silverman GJ;Clancy RM;Izmirly PM;Buyon JP;Reizis B
通讯作者：
Reizis B