Tumor-Infiltrating Immune Cell Landscapes in the Lymph Node Metastasis of Papillary Thyroid Cancer

Regional lymph node metastasis (LNM) increases the risk of distant metastasis in papillary thyroid cancer (PTC) patients. However, it remains unclear how tumor cells in PTC patients with LNM evade immune system surveillance and proceed to colonize distant organs. Here, we comprehensively characterize the tumor-infiltrating immune cell landscape in PTC with LNM. LNM-related genes include multiple important soluble mediators such as CXCL6, IL37, MMP10, and COL11A1, along with genes involved in areas such as extracellular matrix organization and TLR regulation by endogenous ligands. In PTC without LNM, the tumor infiltration of activated dendritic cells and M0 macrophages showed increases from normal cells, but with yet greater increases and correspondingly worse prognosis in PTC with LNM. Conversely, the tumor infiltration of activated NK cells and eosinophils was decreased in PTC without LNM, as compared to normal cells, and yet further decreased in PTC with LNM, with such decreases associated with poor prognosis. We further demonstrate that mutations of driver genes in tumor cells influence the infiltration of surrounding immune cells in the tumor microenvironment (TME). Particularly, patients carrying TG mutations tend to show increased filtration of M2 macrophages and activated NK cells in the TME, whereas patients carrying HRAS mutations tend to show reduced filtration of M0 macrophages and show enhanced filtration of activated dendritic cells in the TME. These findings increase our understanding of the mechanisms of regional lymph node metastasis in PTC and its associated tumor microenvironment, potentially facilitating the development of personalized treatment regimens to combat immunotherapy failure.