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J Cancer 2023; 14(1):72-87. doi:10.7150/jca.59730 This issue Cite

Research Paper

Integrative Analysis Identified CD38 As a Key Node That Correlates Highly with Immunophenotype, Chemoradiotherapy Resistance, And Prognosis of Head and Neck Cancer

Zhengxi He^1,2,3,4*, Chunxue Yue^5*, Xiuwen Chen⁶, Xin Li⁷, Li Zhang⁸, Shan Tan⁸, Xia Yi⁸, Gengqiu Luo^9✉, Yanhong Zhou^1,2,4✉

1. Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University Changsha, Hunan, 410013, China.
2. NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China.
3. Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
4. Cancer Research Institute, Basic School of Medicine, Central South University, Changsha, Hunan, 410011, China.
5. Department of Otolaryngology-Head and Neck Surgery, Shandong Provincial ENT Hospital, Jinan, Shandong, 250022, China.
6. Teaching and Research Section of Clinical Nursing, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
7. Breast Cancer Center, Department of General Surgery, Xiangya Hospital, Central South University, Changsha, Hunan, 410008, China.
8. Changsha Medical University, Changsha, Hunan, 410219, China.
9. Department of Pathology, Xiangya Hospital, Basic School of Medicine, Central South University, Changsha, Hunan, 410008, China.
*These authors contributed equally to this work.

✉ Corresponding author: Professor Yanhong Zhou, NHC Key Laboratory of Carcinogenesis, Hunan Cancer Hospital and The Affiliated Cancer Hospital of Xiangya School of Medicine, Central South University, Changsha, Hunan, 410013, China; E-mail: zhouyanhongedu.cn. Dr Gengqiu Luo, Department of Pathology, Xiangya Hospital, Basic School of Medicine, Central South University, 88 Xiangya Road, Changsha, Hunan 410008, P.R. China; E-mail: luogengqiuedu.cn. More

Abstract

Head and neck cancer (HNC) is mainly treated by surgery, radiotherapy, and adjuvant chemotherapy; however, the prognosis of some patients with HNC is poor because of radiotherapy and chemotherapy resistance. In recent years, anti‑PD‑1 monoclonal antibodies have shown certain efficacy, and a change of the tumor immune microenvironment is the main reason for the failure of HNC immunotherapy. The present study aimed to identify and verify that CD38, which is closely related to the prognosis of HNC, is a potential biological marker of radiotherapy and chemotherapy resistance and PD-L1 immunotherapy resistance via a comprehensive bioinformatic analysis in The Cancer Genome Atlas and Gene Expression Omnibus databases. According to the UALCAN database, the transcript level of CD38 in HNC was analyzed using cluster analysis, and the expression of CD38 mRNA in HNC was detected using the Oncomine database. The characteristics of CD38-related oncogenes were identified by gene cluster enrichment analysis in LinkedOmics. The R2 and SEER databases were used to further evaluate the prognostic significance of the CD38 gene in HNC using receiver operating characteristic curve analysis of Kaplan-Meier (KM) survival and the clinical characteristics of the subjects. The protein-protein interaction network of the top 50 genes showing significant positive correlations with CD38 in HNC was analyzed using STRING. Finally, we used a nasopharyngeal carcinoma (NPC) cell line to verify the biological function. The results showed that the levels of CD38 mRNA expression in patients with HNC were significantly higher than those in healthy controls. The levels of CD38 mRNA expression in patients with HNC of different ages, sexes, and races were significantly higher than those in the healthy controls. CD38 is an independent prognostic factor for HNC, and high expression of CD38 indicates poor prognosis. CD38 expression correlated positively with the markers of many kinds of immune cells, and correlated significantly with the expression of PD-L1. We found that the high expression of CD38 suggested a poor prognosis in the subgroup of tumors treated with chemotherapeutic drugs in the G1/S phase. We used HNC cell lines to verify that the high expression of CD38 promoted the proliferation of NPC cells and produced radiotherapy tolerance. Through comprehensive bioinformatics analysis, we suggested that CD38 is a key gene involved in radiotherapy, chemotherapy, and immune drug resistance in HNC. This study provides a reliable biomarker to predict the prognosis of patients with HNC and a reference for clinical comprehensive treatment of HNC. Individualization combined with CD38 monoclonal antibodies might provide a promising treatment strategy for this fatal disease, and this comprehensive treatment might reduce the damage to normal tissue and improve the prognosis and quality of life of patients with HNC.

Keywords: HNC, Head and neck cancer, CD38, Radioresistance, PD-1/PD-L1, Prognosis

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