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_H1, T_H17, 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.

头颈部鳞状细胞癌（HNSCC）是一种常见的癌症，其5年生存率约为57％，转移是导致死亡的主要原因。尚未完全了解影响HNSCC肿瘤发展和转移的宿主来源的免疫学因素。我们使用侵袭性和转移性HNSCC细胞系LY2（在原位注入野生型（WT）颊颊沟和STAT4不足（Stat4^-/-）BALB / c小鼠。死者尸检表明Stat4^-/-小鼠表现出与WT小鼠相当的原发肿瘤生长。然而，淋巴结和肺转移的比率和程度Stat4^-/-小鼠明显更高。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，并且转移性引流淋巴结中有粒细胞MDSC亚群的积累Stat4^-/-小鼠。此外，我们观察到荷瘤中的T _H 1，T _H 17和细胞毒性活性显着降低Stat4^{- / -}比野生型小鼠。我们的结果表明，STAT4介导了对HNSCC转移的抵抗力，并且STAT4的激活可以潜在地减轻HNSCC患者的淋巴转移。