Abstract
Immunotherapy has been demonstrated as a promising strategy in controlling head and neck squamous cell carcinoma (HNSC). The AID/APOBEC family is well characterized as DNA mutator and considered to play critical roles in immune responses in HNSC. However, the expression pattern and deamination-dependent demethylation roles of AID/APOBECs in HNSC are unclear. In this study, the RNA-seq and DNA methylation profiles of HNSC from TCGA database and cell-based experiments were applied to analyze the relationships between AID/APOBEC expression levels, patients' clinical outcomes, methylation alterations, and immune responses. Here, we found that APOBEC3H was abnormally upregulated in HNSC patients. HPV+ patients tended to have higher APOBEC3H levels than HPV- patients. Remarkably, patients with high APOBEC3H levels showed a favorable overall survival. Furthermore, tumors with high APOBEC3H levels exhibited a genome-wide DNA hypomethylation pattern. APOBEC3H was identified to demethylate and upregulate CXCL10 and improve CD8+ T cell tumor infiltration in the tumor microenvironment. Collectively, APOBEC3H plays critical roles in CD8+ T cell immune infiltration and activation in HNSC, which may be a potential biomarker for oncoimmunotherapy in HNSC.
Highlights
Head and neck cancer (HNC), which encompasses a group of malignancies arising from the upper digestive tract, salivary glands, and thyroid, is the sixth most common cancer in the world
The results showed that 2 out of 9 AID/APOBECs (APOBEC3A, APOBEC3B, APOBEC3D, APOBEC3G, and APOBEC3H) were upregulated, and 2 out of 9 AID/APOBECs (APOBEC2 and AID) were downregulated (Figure 1)
Human papillomavirus (HPV)+ head and neck squamous cell carcinoma (HNSC) were reported to possess the highest burden of AID/APOBEC mutagenesis [31], leading us to hypothesize that HPV infection may be associated with AID/APOBEC abnormal expression patterns in HNSC
Summary
Head and neck cancer (HNC), which encompasses a group of malignancies arising from the upper digestive tract, salivary glands, and thyroid, is the sixth most common cancer in the world. A novel role of genomic cytosine demethylation activity has been reported in several AID/APOBEC family members [16]. AID/APOBEC enzymes play critical roles in several cellular biological processes and pathological progression They could initiate viral genome mutations, antibody somatic hypermutation, or class switching through targeting host genome immunoglobulin loci, which are essential for both adaptive and innate immune responses such as antiviral, B cell affinity maturation, or B cell class switch recombination [11, 12]. Besides the mutagenesis activity, the biological functions and mechanisms of AID/APOBEC deaminases in HNSC progression remain largely unclear and need to be further elucidated. APOBEC3Hmediated CXCL10 demethylation and expression might be responsible for CD8+ T cell infiltration and activation in HNSC, demonstrating a potential role of APOBEC3H in HNSC immunotherapy
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