Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC
Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC
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DOI：
10.3389/fimmu.2019.03095
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发表时间：
2020-01-15
影响因子：
7.3
通讯作者：
Oghumu, Steve
中科院分区：
文献类型：
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作者：
Anderson, Kelvin;Ryan, Nathan;Oghumu, Steve
头颈鳞状细胞癌 (HNSCC) 是一种常见的癌症，5 年生存率约为 57%，转移是导致死亡的主要原因。影响 HNSCC 肿瘤发展和转移的宿主源性免疫因素尚不完全清楚。我们使用侵袭性和转移性 HNSCC 细胞系 LY2 研究了宿主源性信号转导器和转录激活剂 4 (STAT4) 在实验性 HNSCC 过程中的作用，该细胞系原位注射到野生型 (WT) 和 STAT4 缺陷型 (Stat4(-/-)) BALB/c 小鼠的颊沟中。最终处死时进行的尸检显示，Stat4(-/-)小鼠表现出与WT小鼠相当的原发性肿瘤生长。然而，Stat4(-/-)小鼠的淋巴结和肺转移率和范围明显更高。对原发肿瘤、引流淋巴结、脾脏和骨髓进行的下游分析显示，淋巴细胞免疫抑制生物标志物显着上调，以及转移性 Stat4(-/-) 小鼠引流淋巴结中粒细胞 MDSC 亚群的积累。此外，我们观察到与 WT 小鼠相比，荷瘤 Stat4(-/-) 小鼠的 T(H)1、T(H)17 和细胞毒活性显着降低。我们的结果表明，STAT4 介导对 HNSCC 转移的抵抗，并且 STAT4 的激活可能会减轻 HNSCC 患者的淋巴转移。
Head and neck squamous cell carcinoma (HNSCC) is a prevalent form of cancer with 5-years survival rates around 57%, and metastasis is a leading cause of mortality. Host-derived immunological factors that affect HNSCC tumor development and metastasis are not completely understood. We investigated the role of host-derived signal transducer and activator of transcription 4 (STAT4) during experimental HNSCC using an aggressive and metastatic HNSCC cell line, LY2, which was orthotopically injected into the buccal sulcus of wild type (WT) and STAT4 deficient (Stat4(-/-)) BALB/c mice. Necropsies performed at terminal sacrifice revealed that Stat4(-/-) mice displayed comparable primary tumor growth to the WT mice. However, the rate and extent of lymph node and lung metastasis among Stat4(-/-) mice was significantly higher. Downstream analyses performed on primary tumors, draining lymph nodes, spleens and bone marrow revealed significant upregulation of lymphocytic immunosuppressive biomarkers as well as an accumulation of granulocytic MDSC subpopulations in draining lymph nodes of metastatic Stat4(-/-) mice. Further, we observed a significant decrease in T(H)1, T(H)17, and cytotoxic activity in tumor bearing Stat4(-/-) compared to WT mice. Our results demonstrate that STAT4 mediates resistance to HNSCC metastasis, and activation of STAT4 could potentially mitigate lymphatic metastasis in HNSCC patients.