Molecular Subtypes Based on Cell Differentiation Trajectories in Head and Neck Squamous Cell Carcinoma: Differential Prognosis and Immunotherapeutic Responses

Zhen-Dong Huang,Lu-Lu Lin,Yong-Cheng Fu,Ren-Xiong Wei,Zi-Zhen Liu,Hui-Yun Gu,Yan-Yi Liu,Chao Hu

doi:10.3389/fimmu.2021.791621

Abstract

ObjectiveHead and neck squamous cell carcinoma (HNSCC) is one of the most common and lethal malignant tumors. We aimed to investigate the HNSCC cell differentiation trajectories and the corresponding clinical relevance.MethodsBased on HNSCC cell differentiation-related genes (HDRGs) identified by single-cell sequencing analysis, the molecular subtypes and corresponding immunity, metabolism, and stemness characteristics of 866 HNSCC cases were comprehensively analyzed. Machine-learning strategies were used to develop a HNSCC cell differentiation score (HCDscore) in order to quantify the unique heterogeneity of individual samples. We also assessed the prognostic value and biological characteristics of HCDscore using the multi-omics data.ResultsHNSCCs were stratified into three distinct molecular subtypes based on HDRGs: active stroma (Cluster-A), active metabolism (Cluster-B), and active immune (Cluster-C) types. The three molecular subtypes had different characteristics in terms of biological phenotype, genome and epigenetics, prognosis, immunotherapy and chemotherapy responses. We then demonstrated the correlations between HCDscore and the immune microenvironment, subtypes, carcinogenic biological processes, genetic variation, and prognosis. The low-HCDscore group was characterized by activation of immunity, enhanced response to anti-PD-1/PD-L1 immunotherapy, and better survival compared to the high-HCDscore group. Finally, by integrating the HCDscore with prognostic clinicopathological characteristics, a nomogram with strong predictive performance and high accuracy was constructed.ConclusionsThis study revealed that the cell differentiation trajectories in HNSCC played a nonnegligible role in patient prognosis, biological characteristics, and immune responses. Evaluating cancer cell differentiation will help to develop more effective immunotherapy, metabolic therapy, and chemotherapy strategies.

Highlights

Head and neck squamous cell carcinomas (HNSCCs) are derived from the mucosal epithelium in the oral cavity, oropharynx, and larynx, and they are mainly associated with tobacco and alcohol consumption [1]
A single-cell RNA-seq dataset from the GSE103322 was subjected to quality control processing and the normalization to exclude nonconforming cells (Figure 1B)
There was no correlation between mitochondrial gene sequences and sequencing depth (Figure 1C)

Summary

Introduction

Head and neck squamous cell carcinomas (HNSCCs) are derived from the mucosal epithelium in the oral cavity, oropharynx, and larynx, and they are mainly associated with tobacco and alcohol consumption [1]. There are high recurrence and metastasis rates even after surgical resection due to invasion and metastasis, and the 5-year survival rate of HNSCC patients is only about 40–50%. Chemotherapy, radiation, and combination therapy have been used for the clinical management of HNSCC, but long-term survival rates for most patients with advanced HNSCC remain low. Immunotherapy, such as PD-1 inhibitors and CXCR1/2 inhibitors, has become one of the most promising treatments for HNSCC [3]. More research on molecular subtypes is needed to help accurately determine the heterogeneity subtype of HNSCC patients to identify which patients will respond to immunotherapy [5]

Methods

Results

Conclusion