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

BMC Cancer

Xiaofang Liu¹  Wei Cao²  Wenkai Zhou²  Zheqi Liu²  Xuejie Li³ 

[1] Department of Neurology, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, People’s Republic of China;Department of Oral and Maxillofacial & Head and Neck, Oncology, Shanghai Ninth People’s Hospital, Shanghai Jiao Tong University School of Medicine, 200011, Shanghai, People’s Republic of China;National Center for stomatology, National Clinical Research Center For Oral diseases, Shanghai Key Laboratory of Stomatology, 200011, Shanghai, People’s Republic of China;Department of Oral and Maxillofacial Surgery, The First Affiliated Hospital of Zhengzhou University, 450052, Zhengzhou, People’s Republic of China;

关键词: Tongue and mouth floor SCC;    Th2 cells;    CCL22;    NOTCH1;    TCGA;   

DOI  :  10.1186/s12885-021-08671-1

来源: Springer

【 摘 要 】

ObjectiveTongue 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 methodsTranscriptome 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.ResultsIn 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.ConclusionIn 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.

【 授权许可】

CC BY