Targeting glycan sulfation in a CD11c+ myeloid population inhibits early KRAS-mutant lung neoplasia.
Targeting glycan sulfation in a CD11c+ myeloid population inhibits early KRAS-mutant lung neoplasia.
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DOI：
10.1016/j.neo.2021.09.008
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发表时间：
2021-11
期刊：
影响因子：
--
通讯作者：
Fuster MM
中科院分区：
文献类型：
--
作者：
Kim SY;Johns SC;Gupta P;Varki N;Fuster MM
早期肺癌的发展可能受到促进肿瘤生长和侵袭的先天宿主细胞机制的调节。我们最近发现了针对抗原呈递细胞（APCs）的糖基硫酸化酶n -去乙酰化酶/ n -硫转移酶-1 （Ndst1；参与硫酸肝素生物合成）的功能缺失突变如何增强获得性抗肿瘤T细胞免疫机制。将该突变（Ndst1f/f CD11cCre+）杂交到可诱导的自发性Kras突变肺癌模型上[CCSP-rtTA；（tetO7） CMV-Kras-G12D]使我们能够研究APC突变如何影响早期肺癌的形成和生长。我们在模型中检查了早期支气管中心性腺瘤的形成，在突变背景下，这种事件的频率显着降低。这与肿瘤相关的FOXP3+细胞浸润和CD163+ m2型巨噬细胞浸润的显著减少有关。这些发现是在效应CD8+ T细胞浸润到肿瘤之前形成的。这种独特的多糖低硫突变对抑制早期Kras G12D突变支气管中心腺瘤形成的影响，以及参与抑制t调节细胞信号传导（FOXP3+细胞）或肿瘤允许M2巨噬细胞功能（CD163+细胞）的细胞浸润受到抑制的细胞表型，为早期肺肿瘤发展过程中多糖靶向如何调节先天细胞机制提供了新的见解。这些发现也可能影响未来以宿主为中心的免疫抗肿瘤治疗策略的设计。
Early lung carcinoma development may be modulated by innate host cellular mechanisms that promote tumor growth and invasion. We recently identified how a loss-of-function mutation in the glycan sulfating enzyme N-deacetylase/N-sulfotransferase-1 (Ndst1; involved in heparan sulfate biosynthesis) targeted to antigen presenting cells (APCs) may augment acquired anti-tumor T cell immune mechanisms. Crossing this mutation (Ndst1f/f CD11cCre+) onto a model of inducible spontaneous Kras mutant lung cancer [CCSP-rtTA; (tetO7) CMV-Kras-G12D] allowed us to examine how the APC mutation affects the formation and growth of early lung carcinoma. We examined early bronchocentric adenoma formation in the model, and the frequency of such events was significantly reduced on the mutant background. This was associated with significant reductions in tumor associated FOXP3+ cellular infiltration and CD163+ M2-type macrophage infiltration. The findings evolved prior to effector CD8+ T cell infiltration into tumors. The impact of this unique glycan under-sulfating mutation on inhibiting early Kras G12D mutant bronchocentric adenoma formation along with a cellular phenotype of inhibited tumor infiltration by cells involved in suppressive T-regulatory cell signaling (FOXP3+ cells) or tumor-permissive M2 macrophage functions (CD163+ cells) provides insight on how glycan targeting may modulate innate cellular mechanisms during early lung tumor development. The findings may also impact the future design of host-centered immunologic anti-tumor therapeutic strategies.
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影响因子：
50.3
作者：
Dong, Lihui;Chen, Chuanyuan;Han, Dali
通讯作者：
Han, Dali
影响因子：
24.3
作者：
Ohri, C. M.;Shikotra, A.;Bradding, P.
通讯作者：
Bradding, P.
DOI：
10.4049/jimmunol.1600576
发表时间：
2016-12-01
期刊：
Journal of immunology (Baltimore, Md. : 1950)
影响因子：
--
作者：
Busch SE;Hanke ML;Kargl J;Metz HE;MacPherson D;Houghton AM
通讯作者：
Houghton AM
影响因子：
3.7
作者：
Granville CA;Memmott RM;Balogh A;Mariotti J;Kawabata S;Han W;Lopiccolo J;Foley J;Liewehr DJ;Steinberg SM;Fowler DH;Hollander MC;Dennis PA
通讯作者：
Dennis PA
影响因子：
15.3
作者：
Etzerodt, Anders;TsaLkitzi, Kyriaki;Lawrence, Toby
通讯作者：
Lawrence, Toby