黑色素瘤细胞中的 CCL21-Ser 表达将 CCR7+ 初始 T 细胞招募到肿瘤组织并促进肿瘤生长,Cancer Science

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黑色素瘤细胞中的 CCL21-Ser 表达将 CCR7+ 初始 T 细胞招募到肿瘤组织并促进肿瘤生长
Cancer Science ( IF 4.5 ) Pub Date : 2023-07-08 , DOI: 10.1111/cas.15902
Megumi Miyamoto ₁ , Yuki Kawato ₂ , Ryonosuke Fujie ₁ , Kaoru Kurowarabe ₁ , Kakeru Fujiwara ₁ , Reika Nobusawa ₁ , Ryota Hayashi ₁ , Kei Iida _{1,

2} , Izumi Ohigashi ₃ , Haruko Hayasaka _{1,

2,

4}

Affiliation

CCL21-Ser是由Ccl21a基因编码的趋化因子，在次级淋巴器官的胸腺上皮细胞和基质细胞中组成型表达。它通过其受体 CCR7 调节免疫细胞的迁移和存活。在此，使用表达 CCL21-Ser 的黑色素瘤细胞和Ccl21a缺陷小鼠，我们证明了癌细胞来源的 CCL21-Ser 在体内黑色素瘤生长中的功能作用。与野生型小鼠相比，Ccl21a缺陷小鼠的 B16-F10 肿瘤生长显着减少，表明宿主来源的 CCL21-Ser 有助于体内黑色素瘤增殖。在Ccl21a缺陷小鼠中，表达CCL21-Ser的黑色素瘤细胞的肿瘤生长显着增强，这表明来自黑色素瘤细胞的CCL21-Ser在缺乏宿主来源的CCL21-Ser的情况下促进肿瘤生长。肿瘤生长的增加与肿瘤组织中CCR7 ⁺ CD62L ⁺ T 细胞频率的增加相关，但与 Treg 频率呈负相关，表明初始 T 细胞主要促进肿瘤生长。过继转移实验表明，初始 T 细胞优先从血液中招募到具有黑色素瘤细胞衍生的 CCL21-Ser 表达的肿瘤中。^{这些结果表明，来自黑色素瘤细胞的 CCL21-Ser 促进 CCR7 +}幼稚 T 细胞浸润到肿瘤组织中，并创造有利于黑色素瘤生长的肿瘤微环境。

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CCL21-Ser expression in melanoma cells recruits CCR7+ naïve T cells to tumor tissues and promotes tumor growth

CCL21-Ser, a chemokine encoded by the Ccl21a gene, is constitutively expressed in the thymic epithelial cells and stromal cells of secondary lymphoid organs. It regulates immune cell migration and survival through its receptor CCR7. Herein, using CCL21-Ser-expressing melanoma cells and the Ccl21a-deficient mice, we demonstrated the functional role of cancer cell-derived CCL21-Ser in melanoma growth in vivo. The B16-F10 tumor growth was significantly decreased in Ccl21a-deficient mice compared with that in wild-type mice, indicating that host-derived CCL21-Ser contributes to melanoma proliferation in vivo. In Ccl21a-deficient mice, tumor growth of melanoma cells expressing CCL21-Ser was significantly enhanced, suggesting that CCL21-Ser from melanoma cells promotes tumor growth in the absence of host-derived CCL21-Ser. The increase in tumor growth was associated with an increase in the CCR7⁺ CD62L⁺ T cell frequency in the tumor tissue but was inversely correlated with Treg frequency, suggesting that naïve T cells primarily promote tumor growth. Adoptive transfer experiments demonstrated that naïve T cells are preferentially recruited from the blood into tumors with melanoma cell-derived CCL21-Ser expression. These results suggest that CCL21-Ser from melanoma cells promotes the infiltration of CCR7⁺ naïve T cells into the tumor tissues and creates a tumor microenvironment favorable for melanoma growth.

更新日期：2023-07-08

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