Downregulation of CCL22 and mutated NOTCH1 in tongue and mouth floor squamous cell carcinoma results in decreased Th2 cell recruitment and expression, predicting poor clinical outcome

Abstract

Objective Tongue and mouth floor squamous cell carcinoma (T/MF SCC) exhibits a high rate of local recurrence and cervical lymph node metastasis. The effect of the tumor microenvironment on T/MF SCC remains unclear. Materials and methods Transcriptome and somatic mutation data of patients with T/MF SCC were obtained from HNSC projects of the Cancer Genome Atlas. Immune infiltration quantification in early- (clinical stage I–II) and advanced-stage (clinical stage III–IV) T/MF SCC was performed using single sample Gene Set Enrichment Analysis and MCPcounter. Differentially expressed gene data were filtered, and their function was assessed through Gene Ontology and Kyoto Encyclopedia of Genes and Genomes analyses. Kaplan–Meier survival curve analysis and Cox regression model were conducted to evaluate the survival of patients with the CCL22 signature. Maftools was used to present the overview of somatic mutations. Results In T/MF SCC, T helper (Th)2 cell counts were significantly increased in patients with early-stage disease compared to those with advanced-stage disease. Expression of the Th2 cell-related chemokine, CCL22, was downregulated in patients with advanced-stage T/MF SCC. Univariate and multivariate Cox analyses revealed that CCL22 was a good prognostic factor in T/MF SCC. A nomogram based on the expression of CCL22 was constructed to serve as a prognostic indicator for T/MF SCC. NOTCH1 mutations were found at a higher rate in patients with advanced-stage T/MF SCC than in those with early-stage T/MF SCC, resulting in the inhibition of the activation of the NOTCH1-Th2 cell differentiation pathway. The expression levels of CCL22, GATA-3, and IL4 were higher in patients with early-stage T/MF SCC than in those with advanced-stage T/MF SCC. Conclusion In T/MF SCC, high expression of CCL22 may promote the recruitment of Th2 cells and help predict a better survival. Mutations in NOTCH1 inhibit the differentiation of Th2 cells, facilitating tumor progression through a decrease in Th2 cell recruitment and differentiation.

Comprehensive analyses identify RIPOR2 as a genomic instability-associated immune prognostic biomarker in cervical cancer

“…CCL22, a protein secreted by M2 macrophages, recruits Th2 cells, resulting in better survival (48). The gathering effect seems to work on Treg cells as well; however, it shows a contrary influence in CC (49,50). Consistent with our results, PAMR1 has long been considered an inhibitor of tumor activities such as spread, migration, and development in CC.…”

Identification and Biological Validation of a Chemokine/Chemokine Receptor-Based Risk Model for Predicting Immunotherapeutic Response and Prognosis in Head and Neck Squamous Cell Carcinoma

“…We also found that CCL22 was commonly expressed on TME cells of HNSCC in the scRNA-seq analysis. CCL22 has been detected as frequently overexpressed in malignant cells of HNSCC [ 37 , 38 , 39 ]. The high expression of CCL22 contributed to the lymph node metastasis of HNSCC [ 37 ].…”

An Immune-Related Gene Signature Can Predict Clinical Outcomes and Immunotherapeutic Response in Oral Squamous Cell Carcinoma

“…CCL22, mainly synthesized by M2 macrophages, contributes to a deterioration of clinical outcomes of patients with tongue SCC ( Kimura et al, 2019 ). CCL22 downregulation in tongue and mouth floor SCC triggers reduced Th2 cell recruitment and expression and predicts undesirable survival outcomes ( Li et al, 2021 ). Cancer-associated fibroblast-secreted IL-1β may activate CCL22 signaling in oral cancer ( Huang et al, 2019 ).…”