Comprehensive Analyses Reveal Effects on Tumor Immune Infiltration and Immunotherapy Response of APOBEC Mutagenesis and Its Molecular Mechanisms in Esophageal Squamous Cell Carcinoma

Yang, Jie; Xiang, Tao; Zhu, Shihao; Lao, Yueqiong; Wang, Yuqian; Liu, Tianyuan; Li, Kai; Ma, Yuling; Zhong, Ce; Zhang, Shaosen; Tan, Wen; Lin, Dongxin; Wu, Chen

doi:10.7150/ijbs.83824

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International Journal of Medical Sciences

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Int J Biol Sci 2023; 19(8):2551-2571. doi:10.7150/ijbs.83824 This issue Cite

Research Paper

Comprehensive Analyses Reveal Effects on Tumor Immune Infiltration and Immunotherapy Response of APOBEC Mutagenesis and Its Molecular Mechanisms in Esophageal Squamous Cell Carcinoma

Jie Yang^1,#, Tao Xiang^1,#, Shihao Zhu¹, Yueqiong Lao¹, Yuqian Wang¹, Tianyuan Liu¹, Kai Li¹, Yuling Ma¹, Ce Zhong¹, Shaosen Zhang¹, Wen Tan¹, Dongxin Lin^1,2,3,4,✉, Chen Wu^1,2,3,5,✉

1. Department of Etiology and Carcinogenesis, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
2. Key Laboratory of Cancer Genomic Biology, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
3. Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing 211166, China
4. Sun Yat-sen University Cancer Center, State Key Laboratory of Oncology in South China, Guangzhou 510060, China
5. CAMS Oxford Institute, Chinese Academy of Medical Sciences, Beijing 100006, China
^#These authors contributed equally to this work

Citation:

Yang J, Xiang T, Zhu S, Lao Y, Wang Y, Liu T, Li K, Ma Y, Zhong C, Zhang S, Tan W, Lin D, Wu C. Comprehensive Analyses Reveal Effects on Tumor Immune Infiltration and Immunotherapy Response of APOBEC Mutagenesis and Its Molecular Mechanisms in Esophageal Squamous Cell Carcinoma. Int J Biol Sci 2023; 19(8):2551-2571. doi:10.7150/ijbs.83824. https://www.ijbs.com/v19p2551.htm

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Abstract

The apolipoprotein B mRNA editing enzyme catalytic polypeptide (APOBEC) mutagenesis is prevalent in esophageal squamous cell carcinoma (ESCC). However, the functional role of APOBEC mutagenesis has yet to be fully delineated. To address this, we collect matched multi-omics data of 169 ESCC patients and evaluate characteristics of immune infiltration using multiple bioinformatic approaches based on bulk and single-cell RNA sequencing (scRNA-seq) data and verified by functional assays. We find that APOBEC mutagenesis prolongs overall survival (OS) of ESCC patients. The reason for this outcome is probably due to high anti-tumor immune infiltration, immune checkpoints expression and immune related pathway enrichment, such as interferon (IFN) signaling, innate and adaptive immune system. The elevated AOBEC3A (A3A) activity paramountly contributes to the footprints of APOBEC mutagenesis and is first discovered to be transactivated by FOSL1. Mechanistically, upregulated A3A exacerbates cytosolic double-stranded DNA (dsDNA) accumulation, thus stimulating cGAS-STING pathway. Simultaneously, A3A is associated with immunotherapy response which is predicted by TIDE algorithm, validated in a clinical cohort and further confirmed in mouse models. These findings systematically elucidate the clinical relevance, immunological characteristics, prognostic value for immunotherapy and underlying mechanisms of APOBEC mutagenesis in ESCC, which demonstrate great potential in clinical utility to facilitate clinical decisions.

Keywords: esophageal squamous cell carcinoma, APOBEC signature, immune, APOBEC3A, immunotherapy

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APA

Yang, J., Xiang, T., Zhu, S., Lao, Y., Wang, Y., Liu, T., Li, K., Ma, Y., Zhong, C., Zhang, S., Tan, W., Lin, D., Wu, C. (2023). Comprehensive Analyses Reveal Effects on Tumor Immune Infiltration and Immunotherapy Response of APOBEC Mutagenesis and Its Molecular Mechanisms in Esophageal Squamous Cell Carcinoma. International Journal of Biological Sciences, 19(8), 2551-2571. https://doi.org/10.7150/ijbs.83824.

ACS

Yang, J.; Xiang, T.; Zhu, S.; Lao, Y.; Wang, Y.; Liu, T.; Li, K.; Ma, Y.; Zhong, C.; Zhang, S.; Tan, W.; Lin, D.; Wu, C. Comprehensive Analyses Reveal Effects on Tumor Immune Infiltration and Immunotherapy Response of APOBEC Mutagenesis and Its Molecular Mechanisms in Esophageal Squamous Cell Carcinoma. Int. J. Biol. Sci. 2023, 19 (8), 2551-2571. DOI: 10.7150/ijbs.83824.

NLM

CSE

Yang J, Xiang T, Zhu S, Lao Y, Wang Y, Liu T, Li K, Ma Y, Zhong C, Zhang S, Tan W, Lin D, Wu C. 2023. Comprehensive Analyses Reveal Effects on Tumor Immune Infiltration and Immunotherapy Response of APOBEC Mutagenesis and Its Molecular Mechanisms in Esophageal Squamous Cell Carcinoma. Int J Biol Sci. 19(8):2551-2571.

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