Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression.
Rapid Depletion of Intratumoral Regulatory T Cells Induces Synchronized CD8 T- and NK-cell Activation and IFNγ-Dependent Tumor Vessel Regression.
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DOI：
10.1158/0008-5472.can-20-2673
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发表时间：
2021-06-01
期刊：
影响因子：
11.2
通讯作者：
Sato N
中科院分区：
文献类型：
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作者：
Kurebayashi Y;Olkowski CP;Lane KC;Vasalatiy OV;Xu BC;Okada R;Furusawa A;Choyke PL;Kobayashi H;Sato N
已知调节性T细胞(Tregs)抑制抗肿瘤免疫，但肿瘤内Tregs促进肿瘤生长的具体机制尚不清楚。为了更好地了解肿瘤内Tregs的作用，我们使用抗CD25-F(ab‘)2近红外线光免疫疗法(NIR-PIT)选择性地耗尽了肿瘤浸润性Tregs。去除肿瘤浸润性树突状细胞可诱导CD8T细胞和自然杀伤细胞(NK)瞬时但同步表达干扰素-γ。尽管受检肿瘤中含有少量CD8T和NK细胞，但这些CD8T和NK细胞产生的干扰素-γ可导致肿瘤血管快速消退、瘤内缺血、肿瘤坏死/凋亡和生长抑制。这些作用需要血管内皮细胞表达干扰素-γ受体。在荷瘤的Foxp3DTR小鼠体内系统Treg耗尽的早期阶段也观察到了类似的结果；与IL-15联合治疗进一步抑制了肿瘤的生长，并实现了更快的完全消退。这些结果表明，肿瘤内Treg通过抑制CD8T和NK细胞产生干扰素-γ，在维持肿瘤血管和肿瘤生长方面起着关键作用，为Treg靶向治疗的机制提供了深入的了解。
Regulatory T cells (Tregs) are known to inhibit anti-tumor immunity, yet the specific mechanism by which intratumoral Tregs promote tumor growth remains unclear. To better understand the roles of intratumoral Tregs, we selectively depleted tumor-infiltrating Tregs using anti-CD25-F(ab′)2 near-infrared photoimmunotherapy (NIR-PIT). Depletion of tumor-infiltrating Tregs induced transient but synchronized IFN-γ expression in CD8 T and natural killer (NK) cells. Despite the small fraction of CD8 T and NK cells contained within examined tumors, IFN-γ produced by these CD8 T and NK cells led to efficient and rapid tumor vessel regression, intratumoral ischemia, and tumor necrosis/apoptosis and growth suppression. IFN-γ receptor expression on vascular endothelial cells was required for these effects. Similar findings were observed in the early phase of systemic Treg depletion in tumor-bearing Foxp3DTR mice; combination with IL-15 therapy further inhibited tumor growth and achieved increased complete regression. These results indicate the pivotal roles of intratumoral Tregs in maintaining tumor vessels and tumor growth by suppressing CD8 T and NK cells from producing IFN-γ, providing insight into the mechanism of Treg-targeting therapies.