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.

Background: The incidence and recurrence rate of papillary thyroid carcinoma (PTC) are high. Thus, it is critical to accurately identify patients at high risk of recurrence. Pyroptosis is a type of programmed cell death closely related to the progression and prognosis of cancer. However, the role of pyroptosis in PTC remains unclear. Methods: Transcriptome data for PTC patients were obtained from The Cancer Genome Atlas database. The expression level of pyroptosis-related genes (PRGs) in PTC and normal tissues was identified. Based on these differentially expressed genes, a risk score model of disease-free survival (DFS) was established using least absolute shrinkage and selection operator Cox regression. In-cluster and quantitative real-time PCR validations were carried out. A nomogram, in combination with clinical factors, was also established. In addition, its relationship with immune characteristics and tumor gene mutations is discussed. Results: A risk score model with four PRGs, including CASP6, CASP9, IL-18, and NOD1, was established. The samples were divided into high- and low-risk clusters, according to the risk score, revealing significant differences in DFS between the two clusters. A nomogram was established combining age, lymph node metastasis and extrathyroidal extension. The area under the curve (AUC) of predicting one-, five-, and 10-year DFS in PTC patients was 0.745, 0.801, and 0.803, respectively. The low-risk cluster showed higher levels of immune infiltration and immune checkpoint gene expression, while the high-risk cluster demonstrated a higher tumor mutation burden. Conclusion: A predictive DFS model was established, based on PRGs, which may aid in identifying patients at high risk of recurrence. The present study helps to better understand the role of pyroptosis in the progression and prognosis of PTC.

Worldwide, breast cancer is the most common malignancy. LHX2, a member of the LIM homeobox gene family and a transcription factor, plays a crucial role in numerous tumors, but the function of LHX2 in breast cancer progression remains unknown. In this study, we show that LHX2 is upregulated in breast cancer tissues and positively correlated with breast cancer progression. Meanwhile, the clinical characteristics of breast cancer and LHX2 expression showed a strong correlation. GSEA showed that a high LHX2 expression may activate the T-cell activation pathway, PI3K/AKT/mTOR signaling pathway, and apoptosis pathway. Moreover, ssGSEA showed that Th1 cells and Th2 cells had a positive correlation with LHX2 expression in breast cancer. Experiments showed that LHX2 promotes the proliferation, colony formation, migration, and invasion of breast cancer cells. Immunohistochemistry and immunofluorescence assays helped to analyze LHX2-associated immune infiltration in breast cancer. A Western blot assay proved that LHX2 activated the PI3K/AKT/mTOR pathway and the apoptosis pathway. A TUNEL assay confirmed that LHX2 inhibited apoptosis. Taken together, LHX2 plays a vital role in breast cancer’s progression and prognosis and could be an immune infiltration biomarker for breast cancer, and LHX2 activates the PI3K/AKT/mTOR pathway and apoptosis pathway in breast cancer.

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