Immune Suppression Mediated by STAT4 Deficiency Promotes Lymphatic Metastasis in HNSCC

Abstract

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.

An analytical study on the awareness, attitude and practice during the COVID-19 pandemic in Riyadh, Saudi Arabia

“…From the participants' responses, staying at home and isolating the infected individuals ranked the first with 99.7% and 99.9% respectively. These measures have been taken by many countries and have shown to be significantly successful in controlling the spread of the virus [ 26 ]. The second-ranked attitude detected in participants' responses was the closure of universities and schools with around 96%.…”

Recent advances and future directions in anti‐tumor activity of cryptotanshinone: A mechanistic review

“…However, interesting point is the involvement of STAT4 in regulation of immune response. It has been shown that STAT4 knock‐down provides immune escape of cancer cells and ensures their migration and metastasis (Anderson et al, 2019). CT targets JAK2/STAT4 signaling pathway in cancer immunotherapy.…”

Mining database for the expression and clinical significance of STAT family in head and neck squamous cell carcinomas

“…In HNSC, inhibition of STAT3 could lead to greater cetuximab sensitivity [12] . Moreover, activation of STAT4 could potentially mitigate lymphatic metastasis in HNSC [13] . However, the role of STAT family in HNSC was far from fully illuminated.…”

“…For example, inhibition of STAT3 could lead to greater cetuximab sensitivity [12] . Activation of STAT4 could potentially mitigate lymphatic metastasis in HNSC [13] . Moreover, gene-expression signature associated with recurrent disease in HNSC was profiled to clarify the gene expression profile of HNSC[14].…”