scholarly journals At the Crossroads of Molecular Biology and Immunology: Molecular Pathways for Immunological Targeting of Head and Neck Squamous Cell Carcinoma

2021 ◽  
Vol 2 ◽  
Author(s):  
Niels E. Wondergem ◽  
Dennis N. L. M. Nijenhuis ◽  
Jos B. Poell ◽  
C. René Leemans ◽  
Ruud H. Brakenhoff ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Wnt Signaling ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Signaling Pathways ◽  
Squamous Cell ◽  
Immune Evasion ◽  
Neck Squamous Cell Carcinoma ◽  
Disease Etiology ◽  
Mutational Activation

Background: Recent advances in immunotherapy for head and neck squamous cell carcinoma (HNSCC) have led to implementation of anti-programmed death receptor 1 (PD-1) immunotherapy to standard of care for recurrent/metastatic HNSCC. However, the majority of tumors do not respond to these therapies, indicating that these tumors are not immunogenic or other immunosuppressive mechanisms might be at play.Aim: Given their role in carcinogenesis as well as in immune modulation, we discuss the relation between the STAT3, PI3K/AKT/mTOR and Wnt signaling pathways to identify potential targets to empower the immune response against HNSCC.Results: We focused on three pathways. First, STAT3 is often overactivated in HNSCC and induces the secretion of immunosuppressive cytokines, thereby promoting recruitment of immune suppressive regulatory T cells and myeloid-derived suppressor cells to the tumor microenvironment (TME) while hampering the development of dendritic cells. Second, PI3K/AKT/mTOR mutational activation results in increased tumor proliferation but could also be important in HNSCC immune evasion due to the downregulation of components in the antigen-processing machinery. Third, canonical Wnt signaling is overactivated in >20% of HNSCC and could be an interesting pleotropic target since it is related to increased tumor cell proliferation and the development of an immunosuppressive HNSCC TME.Conclusion: The molecular pathology of HNSCC is complex and heterogeneous, varying between sites and disease etiology (i.e., HPV). The in HNSCC widely affected signaling pathways STAT3, PI3K/AKT/mTOR and Wnt are implicated in some of the very mechanisms underlying immune evasion of HNSCC, thereby representing promising targets to possibly facilitate immunotherapy response.

scholarly journals A dual specificity kinase, DYRK1A, as a potential therapeutic target for head and neck squamous cell carcinoma

2016 ◽  
Vol 6 (1) ◽  
Author(s):  
Aneesha Radhakrishnan ◽  
Vishalakshi Nanjappa ◽  
Remya Raja ◽  
Gajanan Sathe ◽  
Vinuth N. Puttamallesh ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Signaling Pathways ◽  
Cell Lines ◽  
Squamous Cell ◽  
Therapeutic Target ◽  
Neck Squamous Cell Carcinoma ◽  
Dual Specificity ◽  
Hnscc Cell

Abstract Despite advances in clinical management, 5-year survival rate in patients with late-stage head and neck squamous cell carcinoma (HNSCC) has not improved significantly over the past decade. Targeted therapies have emerged as one of the most promising approaches to treat several malignancies. Though tyrosine phosphorylation accounts for a minority of total phosphorylation, it is critical for activation of signaling pathways and plays a significant role in driving cancers. To identify activated tyrosine kinase signaling pathways in HNSCC, we compared the phosphotyrosine profiles of a panel of HNSCC cell lines to a normal oral keratinocyte cell line. Dual-specificity tyrosine-(Y)-phosphorylation regulated kinase 1A (DYRK1A) was one of the kinases hyperphosphorylated at Tyr-321 in all HNSCC cell lines. Inhibition of DYRK1A resulted in an increased apoptosis and decrease in invasion and colony formation ability of HNSCC cell lines. Further, administration of the small molecular inhibitor against DYRK1A in mice bearing HNSCC xenograft tumors induced regression of tumor growth. Immunohistochemical labeling of DYRK1A in primary tumor tissues using tissue microarrays revealed strong to moderate staining of DYRK1A in 97.5% (39/40) of HNSCC tissues analyzed. Taken together our results suggest that DYRK1A could be a novel therapeutic target in HNSCC.

scholarly journals Search for mutations in signaling pathways in head and neck squamous cell carcinoma

2013 ◽  
Vol 30 (1) ◽  
pp. 334-340 ◽  
Author(s):  
THAIS GULIM DE CARVALHO ◽  
ANA CAROLINA DE CARVALHO ◽  
DANIELLE CALHEIROS CAMPELO MAIA ◽  
JULIANA KAORI OGAWA ◽  
ANDRE LOPES CARVALHO ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Signaling Pathways ◽  
Squamous Cell ◽  
Neck Squamous Cell Carcinoma

scholarly journals Roles of the Wnt Signaling Pathway in Head and Neck Squamous Cell Carcinoma

2021 ◽  
Vol 7 ◽  
Author(s):  
Jing Xie ◽  
Li Huang ◽  
You-Guang Lu ◽  
Da-Li Zheng
Keyword(s):  
Squamous Cell Carcinoma ◽  
Wnt Signaling ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Signaling Pathway ◽  
Squamous Cell ◽  
Wnt Pathway ◽  
Wnt Signaling Pathway ◽  
Neck Squamous Cell Carcinoma ◽  
Upstream Gene

Head and neck squamous cell carcinoma (HNSCC) is the most common type of head and neck tumor. It is a high incidence malignant tumor associated with a low survival rate and limited treatment options. Accumulating conclusions indicate that the Wnt signaling pathway plays a vital role in the pathobiological process of HNSCC. The canonical Wnt/β-catenin signaling pathway affects a variety of cellular progression, enabling tumor cells to maintain and further promote the immature stem-like phenotype, proliferate, prolong survival, and gain invasiveness. Genomic studies of head and neck tumors have shown that although β-catenin is not frequently mutated in HNSCC, its activity is not inhibited by mutations in upstream gene encoding β-catenin, NOTCH1, FAT1, and AJUBA. Genetic defects affect the components of the Wnt pathway in oral squamous cell carcinoma (OSCC) and the epigenetic mechanisms that regulate inhibitors of the Wnt pathway. This paper aims to summarize the groundbreaking discoveries and recent advances involving the Wnt signaling pathway and highlight the relevance of this pathway in head and neck squamous cell cancer, which will help provide new insights into improving the treatment of human HNSCC by interfering with the transcriptional signaling of Wnt.

scholarly journals The let-7 family of microRNAs suppresses immune evasion in head and neck squamous cell carcinoma by promoting PD-L1 degradation

2019 ◽  
Vol 17 (1) ◽  
Author(s):  
Dan Yu ◽  
Xueshibojie Liu ◽  
Guanghong Han ◽  
Yan Liu ◽  
Xue Zhao ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Squamous Cell ◽  
Immune Evasion ◽  
Neck Squamous Cell Carcinoma ◽  
Host Immune System ◽  
Immune Recognition ◽  
Over Expression

Abstract Background Accumulation of immunosuppressive protein programmed death-ligand 1 (PD-L1) has been documented in several cancers and contributes to the evasion of the host immune system. However, cancer cell-intrinsic signaling-dependent control of PD-L1 expression remains to be elucidated. Herein, we aimed to identify the let-7 family of microRNAs as candidates that up-regulate tumor cell PD-L1 expression and mediates immune evasion of head and neck squamous cell carcinoma (HNSCC). Methods The expression of let-7 family and PD-L1 was quantified in HNSCC tissues and adjacent normal tissues. PD-L1 degradation was evaluated in HNSCC cells in response to elevated expressions of let-7a or let-7b. The regulation of let-7 family on PD-L1 degradation through a mechanism involving T-cell factor-4 (TCF-4) control of β-catenin/STT3 pathway was evaluated. Immune recognition of HNSCC in vivo was examined in subcutaneous tumor-bearing C3H mice in the presence of let-7a/b and/or CTLA-4 antibody. Results The let-7 family were significantly down-regulated in the context of HNSCC, sharing a negative correlation with PD-L1 expression. Glycosylated PD-L1 was detected in HNSCC cells, which was reduced by let-7a/b over-expression. TCF-4, the target of let-7a/b, activated the β-catenin/STT3 pathway and promoted PD-L1 degradation. In vivo analysis demonstrated that let-7a/b over-expression potentiated anticancer immunotherapy by CTLA-4 blockade. Conclusions Taken together, our findings highlight targeting let-7 family as a potential strategy to enhance immune checkpoint therapy for HNSCC.

scholarly journals Clinical significance and biological functions of chemokine CXCL3 in head and neck squamous cell carcinoma

2021 ◽  
Author(s):  
Jian Guan ◽  
Jinru Weng ◽  
Qiaosheng Ren ◽  
Chunbin Zhang ◽  
Liantao Hu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Signaling Pathways ◽  
Squamous Cell ◽  
Tumor Biology ◽  
Mapk Signaling ◽  
Neck Squamous Cell Carcinoma ◽  
Expression Level ◽  
Cox Regression Analysis

CXCL3 plays extensive roles in tumorigenesis in various types of human cancers through its roles in tumor cell differentiation, invasion, and migration. However, the mechanisms of CXCL3 in head and neck squamous cell carcinoma (HNSCC) remains unclear. In our study, multiple databases were used to explore the expression level, prognostic value, and related mechanisms of CXCL3 in human HNSCC through bioinformatic methods. We also performed further experiments in vivo and in vitro to evaluate the expression of CXCL3 in a human head and neck tissue microarray and the underlying effect mechanisms of CXCL3 on the tumor biology of HNSCC tumor cells. The result showed that the expression level of CXCL3 in patients with HNSCC was significantly higher as compared with that in normal tissues (p<0.05). Kaplan-Meier survival analysis demonstrated that patients with high CXCL3 expression had a lower overall survival rate (p=0.038). CXCL3 was further identified as an independent prognostic factor for HNSCC patients by Cox regression analysis, and GSEA exhibited that several signaling pathways including Apoptosis, Toll-like receptor, Nod-like receptor, Jak-STAT, and MAPK signaling pathways may be involved in the tumorigenesis of HNSCC. CAL27 cells overexpressing or HNSCC cells treated with exogenous CXCL3 exhibited enhanced cell malignant behaviors, whereas downregulating CXCL3 expression resulted in decreased malignant behaviors in HSC4 cells. In addition, CXCL3 may affect the expression of several genes, including ERK1/2, Bcl-2, Bax, STAT3, and NF-κB. In summary, our bioinformatics and experiment findings effectively suggest the information of CXCL3 expression, roles, and the potential regulatory network in HNSCC.

scholarly journals Comprehensive Analysis of Mutation-Based and Expressed Genes-Based Pathways in Head and Neck Squamous Cell Carcinoma

Processes ◽  
2021 ◽  
Vol 9 (5) ◽  
pp. 792
Author(s):  
Bhumsuk Keam ◽  
Jin Young Park ◽  
Jinpyo Kim ◽  
Gun Do Kim ◽  
Yunsuk Yu ◽  
...  
Keyword(s):  
Squamous Cell Carcinoma ◽  
Cell Carcinoma ◽  
Head And Neck ◽  
Mrna Expression ◽  
Signaling Pathways ◽  
Squamous Cell ◽  
Checkpoint Inhibitors ◽  
Single Gene ◽  
Genetic Alterations ◽  
Neck Squamous Cell Carcinoma

Over- or under-expression of mRNA results from genetic alterations. Comprehensive pathway analyses based on mRNA expression are as important as single gene level mutations. This study aimed to compare the mutation- and mRNA expression-based signaling pathways in head and neck squamous cell carcinoma (HNSCC) and to match these with potential drug or druggable pathways. Altogether, 93 recurrent/metastatic HNSCC patients were enrolled. We performed targeted gene sequencing using Illumina HiSeq-2500 for NGS, and nanostring nCounter® for mRNA expression; mRNA expression was classified into over- or under-expression groups based on the expression. We investigated mutational and nanostring data using the CBSJukebox® system, which is a big-data driven platform to analyze druggable pathways, genes, and protein-protein interaction. We calculated a Treatment Benefit Prediction Score (TBPS) to identify suitable drugs. By mapping the high score interaction genes to identify druggable pathways, we found highly related signaling pathways with mutations. Based on the mRNA expression and interaction gene scoring model, several pathways were found to be associated with over- and under-expression. Mutation-based pathways were associated with mRNA under-expressed genes-based pathways. These results suggest that HNSCCs are mainly caused by the loss-of-function mutations. TBPS found several matching drugs such as immune checkpoint inhibitors, EGFR inhibitors, and FGFR inhibitors.

Sign in / Sign up

Export Citation Format

Share Document