The viral expression and immune status in human cancers and insights into novel biomarkers of immunotherapy

BMC Cancer. 2021 Nov 5;21(1):1183. doi: 10.1186/s12885-021-08871-9.


Background: Viral infections are prevalent in human cancers and they have great diagnostic and theranostic values in clinical practice. Recently, their potential of shaping the tumor immune microenvironment (TIME) has been related to the immunotherapy of human cancers. However, the landscape of viral expressions and immune status in human cancers remains incompletely understood.

Methods: We developed a next-generation sequencing (NGS)-based pipeline to detect viral sequences from the whole transcriptome and used machine learning algorithms to classify different TIME subtypes.

Results: We revealed a pan-cancer landscape of viral expressions in human cancers where 9 types of viruses were detected in 744 tumors of 25 cancer types. Viral infections showed different tissue tendencies and expression levels. Multi-omics analyses further revealed their distinct impacts on genomic, transcriptomic and immune responses. Epstein-Barr virus (EBV)-infected stomach adenocarcinoma (STAD) and Human Papillomavirus (HPV)-infected head and neck squamous cell carcinoma (HNSC) showed decreased genomic variations, significantly altered gene expressions, and effectively triggered anti-viral immune responses. We identified three TIME subtypes, in which the "Immune-Stimulation" subtype might be the promising candidate for immunotherapy. EBV-infected STAD and HPV-infected HNSC showed a higher frequency of the "Immune-Stimulation" subtype. Finally, we constructed the eVIIS pipeline to simultaneously evaluate viral infection and immune status in external datasets.

Conclusions: Viral infections are prevalent in human cancers and have distinct influences on hosts. EBV and HPV infections combined with the TIME subtype could be promising biomarkers of immunotherapy in STAD and HNSC, respectively. The eVIIS pipeline could be a practical tool to facilitate clinical practice and relevant studies.

Keywords: Immunotherapy; Machine learning; Tumor immune microenvironment (TIME); Viral infections; pan-cancer analysis.

MeSH terms

  • Biomarkers, Tumor / genetics
  • Biomarkers, Tumor / immunology
  • DNA, Viral / genetics
  • Epstein-Barr Virus Infections
  • Genetic Variation
  • Genome, Viral
  • Head and Neck Neoplasms / immunology
  • Head and Neck Neoplasms / therapy
  • Head and Neck Neoplasms / virology
  • Herpesvirus 4, Human / genetics
  • High-Throughput Nucleotide Sequencing / methods
  • Humans
  • Immunotherapy*
  • Kaplan-Meier Estimate
  • Leukocytes / classification
  • Leukocytes / cytology
  • Machine Learning*
  • Mutation
  • Neoplasms* / immunology
  • Neoplasms* / therapy
  • Neoplasms* / virology
  • Oncogenic Viruses* / genetics
  • Oncogenic Viruses* / immunology
  • Papillomaviridae / genetics
  • Papillomavirus Infections
  • RNA-Seq
  • Squamous Cell Carcinoma of Head and Neck / immunology
  • Squamous Cell Carcinoma of Head and Neck / virology
  • Stomach Neoplasms / immunology
  • Stomach Neoplasms / therapy
  • Stomach Neoplasms / virology
  • Support Vector Machine
  • Transcriptome
  • Tumor Microenvironment* / genetics
  • Tumor Microenvironment* / immunology
  • Tumor Virus Infections* / genetics
  • Tumor Virus Infections* / immunology


  • Biomarkers, Tumor
  • DNA, Viral