Department of Medicine, Division of Pulmonary and Critical Care, University of California San Diego, La Jolla, CA, USA; VA San Diego Healthcare System, Medical and Research Sections, La Jolla, CA, USA.
Glycobiology Research and Training Center, University of California San Diego, La Jolla, CA, USA.
Neoplasia. 2021 Nov;23(11):1137-1143. doi: 10.1016/j.neo.2021.09.008. Epub 2021 Oct 26.
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.
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。我们最近确定了一种糖胺聚糖硫酸化酶 N-去乙酰基/N-磺基转移酶 1（参与肝素硫酸合成）功能丧失突变如何靶向抗原呈递细胞（APCs），从而增强获得性抗肿瘤 T 细胞免疫机制。将这种突变（Ndst1f/f CD11cCre+）引入到诱导性自发 Kras 突变肺癌模型[CCSP-rtTA；（tetO7）CMV-Kras-G12D]中，使我们能够研究 APC 突变如何影响早期肺癌的形成和生长。我们检查了模型中早期支气管中心性腺瘤的形成，并且这种事件的频率在突变背景下显著降低。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。这些发现发生在效应 CD8+T 细胞浸润到肿瘤之前。这种独特的聚糖低硫酸化突变对抑制早期 Kras G12D 突变支气管中心性腺瘤形成的影响，以及抑制参与抑制性 T 调节细胞信号（FOXP3+细胞）或肿瘤允许性 M2 巨噬细胞功能（CD163+细胞）的细胞浸润肿瘤的细胞表型，为聚糖靶向如何在早期肺肿瘤发展过程中调节先天细胞机制提供了深入了解。这些发现还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。
