PO.TB10.05 · 肿瘤生物学
衰老通过组织浸润性Treg促进肝和肺黑色素瘤转移
Aging promotes liver and lung melanoma metastasis via tissue-infiltrating Tregs
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摘要 Abstract
中文摘要
转移是黑色素瘤相关死亡的主要原因，但其年龄相关机制仍知之甚少。这一空白部分源于大多数研究依赖年轻小鼠模型（约8周龄，相当于人类20岁）。此外，研究主要聚焦于肺转移，尽管黑色素瘤常扩散至其他部位，如肝脏——肝脏对免疫检查点抑制剂（ICI）的抵抗性显著更强。使用同基因黑色素瘤细胞，我们优化了静脉（IV）注射以模拟肺定植，并利用水动力尾静脉注射开发了一种新颖的肝定植模型。将肿瘤细胞注入年轻（8周）和衰老（12-16个月）雄性C57BL/6小鼠。收获脾脏、肺和肝，通过流式细胞术评估淋巴细胞和髓系群体的免疫浸润。使用苏木精-伊红（H&E）和免疫组织化学（IHC）染色对转移灶进行定量并检查免疫细胞的空间位置。在观察到调节性T细胞（Treg）在衰老小鼠的肺和肝转移部位均持续增加后，我们用抗小鼠CD25抗体（我们表明其减少Treg而不改变CD3+、CD4+或CD8+ T细胞浸润）或IgG对照（200 μg/只，腹腔内注射）处理额外的衰老队列，以评估Treg在转移中的作用。与年轻小鼠相比，衰老显著增加了肺和肝中的黑色素瘤定植。对肺和肝免疫微环境共同变化的分析显示，衰老小鼠的两个转移部位均有升高的Treg浸润。值得注意的是，Treg在转移前龛中未升高，提示一种年龄和肿瘤特异性的免疫抑制机制。使用抗CD25抗体清除衰老小鼠中的Treg，与IgG对照相比显著减少了肺转移。此外，清除Treg减少了转移部位TGF-beta的分泌和髓系细胞数量，并增加了NK1.1+ NK细胞、CD4+和CD8+ T细胞的数量。我们的发现表明，年龄相关的Treg浸润促进向肺和肝的转移，提示靶向Treg可能提供一种有前景的方法来减轻黑色素瘤中年龄相关的转移进展。
查看英文原文 English abstract
Metastasis is the leading cause of melanoma-related deaths, yet its age-related mechanisms remain poorly understood. This gap stems partly from reliance on young mouse models (~8 weeks old, equivalent to 20 human years) in most studies. Additionally, research has largely focused on lung metastasis, even though melanoma often spreads to other sites like the liver, which is notably more resistant to immune checkpoint inhibitors (ICIs).Using syngeneic melanoma cells, we optimized intravenous (IV) injections to model lung colonization and developed a novel liver colonization model using hydrodynamic tail vein injections. Tumor cells were injected into young (8 weeks) and aged (12-16 months) male C57BL/6 mice. Spleen, lungs, and liver were harvested to assess immune infiltration of lymphocyte and myeloid populations via flow cytometry. Hematoxylin and eosin (H&E) and immunohistochemistry (IHC) staining were used to quantify metastases and examine spatial immune cell locations. Upon observation that regulatory T cells (Tregs) increased consistently in aged mice in both lung and liver metastatic sites, we treated additional aged cohorts with either anti-mouse CD25 antibody, which we show decreased Tregs while not changing CD3+, CD4+ or CD8+ T cell infiltration, or an IgG control (200 μg/mouse, intraperitoneally) to evaluate the role of Tregs and in metastasis.Aging significantly increased melanoma colonization in both the lungs and liver compared to young mice. Analysis of common changes in the immune microenvironment of both the lung and the liver revealed elevated Treg infiltration in both metastatic sites of aged mice. Notably, Tregs were not elevated in the pre-metastatic niche, suggesting an age- and tumor-specific mechanism of immune suppression. Depletion of Tregs in aged mice using anti-CD25 antibody significantly reduced lung metastases compared to IgG controls. Moreover, depletion of Tregs decreased secretion of TGF-beta and the number of myeloid cells in metastatic sites and increased the number of NK1.1 + NK cells, CD4 + and CD8 + T cells.Our findings indicate that age-associated Treg infiltration promotes metastasis to the lung and liver, suggesting that targeting Tregs could offer a promising approach to mitigate age-related metastatic progression in melanoma.
利益披露 Disclosure
A. Burtseva, None..
J. Pasamonte, None..
C. Price, None.