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Co-expression of receptor tyrosine kinases and CD8 T-lymphocyte genes is associated with distinct prognoses, immune cell infiltration patterns and immunogenicity in cancers

  • Author Footnotes
    # These authors contributed equally to this work.
    Junyu Long
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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  • Author Footnotes
    # These authors contributed equally to this work.
    Peipei Chen
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Clinical Nutrition and Department of Health Medicine, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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  • Author Footnotes
    # These authors contributed equally to this work.
    Xiaobo Yang
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
    Search for articles by this author
  • Author Footnotes
    # These authors contributed equally to this work.
    Jin Bian
    Footnotes
    # These authors contributed equally to this work.
    Affiliations
    Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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  • Xu Yang
    Affiliations
    Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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  • Anqiang Wang
    Affiliations
    Department of Gastrointestinal Surgery, Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Peking University Cancer Hospital & Institute, Beijing, China
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  • Yu Lin
    Affiliations
    Shenzhen Withsum Technology Limited, Shenzhen, China
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  • Hanping Wang
    Correspondence
    Reprint requests: Haitao Zhao, MD, PhD, Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
    Affiliations
    Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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  • Xinting Sang
    Correspondence
    Reprint requests: Xinting Sang, MD, PhD, Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
    Affiliations
    Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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  • Haitao Zhao
    Correspondence
    Reprint requests: Hanping Wang, MD, PhD, Division of Pulmonary and Critical Care Medicine, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China.
    Affiliations
    Department of Liver Surgery, State Key Laboratory of Complex Severe and Rare Diseases, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences & Peking Union Medical College, Beijing, China
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  • Author Footnotes
    # These authors contributed equally to this work.
Published:December 28, 2022DOI:https://doi.org/10.1016/j.trsl.2022.12.008

      Abstract

      Tumor angiogenesis and the immune microenvironment are 2 essential aspects of the tumor microenvironment (TME). The combination of receptor tyrosine kinase (RTK) inhibitor (TKI)-mediated antiangiogenic therapy and CD8 T-lymphocyte-mediated immunotherapy has become an important focus of cancer treatment, with good results for many tumor types. However, the complex regulatory interactions between these 2 treatment strategies have not been elucidated. Therefore, we systematically investigated the association between the RTKs and CD8 T-lymphocyte genes (CD8Ts) across cancers. We comprehensively evaluated alterations in RTK genes across cancers and examined the co-expression of RTKs and CD8Ts using a weighted gene co-expression network analysis. We found that RTKs exhibited extensive genetic alterations across cancers and were significantly related to the activity of cancer hallmark-related pathways. We identified co-expression between the RTKs and CD8Ts. The low co-expression score subtype was associated with significant better clinical benefits and was characterized by a hot immune microenvironment, including more infiltrating immune cells, higher chemokine expression, and stronger immunogenicity, such as the tumor mutation burden and neoantigens. Two immunotherapy cohorts confirmed that patients with low co-expression scores had an inflamed TME phenotype and significant therapeutic advantages. Then, 4 co-expression patterns were identified, with different patterns reflecting different prognoses and immune microenvironments. The RTKlowCD8Thigh group was associated with the best prognosis and immune-activated microenvironment. In summary, the present study indicates co-expression of RTKs and CD8Ts, which supports the potential application of the combination of inhibiting RTKs activity via TKI-targeted therapy and increasing CD8 T cell activity via immunotherapy in the treatment of cancer.

      Abbreviations:

      ACC (Adrenocortical carcinoma), AJCC (American Joint Committee on Cancer), BCR (B-cell receptor), BLCA (Bladder urothelial carcinoma), BRCA (Breast invasive carcinoma), CD8Ts (CD8 T-lymphocyte genes), CESC (Cervical squamous cell carcinoma and endocervical adenocarcinoma), CHOL (Cholangiocarcinoma), CNV (Copy number variation), COAD (Colon adenocarcinoma), CTLA-4 (Cytotoxic T-lymphocyte-associated protein-4), CYT (Cytolytic activity score), DLBC (Lymphoid neoplasm diffuse large B-cell lymphoma), EGF (Epidermal growth factor), ESCA (Esophageal carcinoma), ESTIMATE (Estimation of stromal and immune cells in malignant tumors using expression data), FGF (Fibroblast growth factor), GBM (Glioblastoma multiforme), GGI (Gene expression grade index), GSCA (Gene set cancer analysis), GSEA (Gene set enrichment analysis), HLA (Human leukocyte antigen), HNSC (Head and neck squamous cell carcinoma), ICI (Immune-checkpoint inhibitor), IFN (Interferon), KICH (Kidney chromophobe), KIRC (Kidney renal clear cell carcinoma), KIRP (Kidney renal papillary cell carcinoma), LAML (Acute myeloid leukemia), LGG (Brain lower grade glioma), LIHC (Liver hepatocellular carcinoma), LUAD (Lung adenocarcinoma), LUSC (Lung squamous cell carcinoma), MESO (Mesothelioma), MHC (Major histocompatibility complex), MM (Module membership), NSCLC (Non-small cell lung cancer), OS (Overall survival), OV (Ovarian serous cystadenocarcinoma), PAAD (Pancreatic adenocarcinoma), PCPG (Pheochromocytoma and paraganglioma), PD-1 (Programmed death-1), PDGF (Platelet-derived growth factor), PD-L1 (Programmed death ligand-1), PRAD (Prostate adenocarcinoma), READ (Rectal adenocarcinoma), RPPA (Reversed-phase protein array), RTK (Receptor tyrosine kinase), SARC (Sarcoma), SKCM (Skin cutaneous melanoma), SNV (Single-nucleotide variation), ssGSEA (Single-sample gene set enrichment analysis), STAD (Stomach adenocarcinoma), TCGA (The Cancer Genome Atlas), TCPA (The Cancer Proteome atlas), TCR (T-cell receptor), TGCT (Testicular germ cell tumors), THCA (Thyroid carcinoma), THYM (Thymoma), TIL (Tumor-infiltrating lymphocyte), TKI (Tyrosine kinase inhibitor), TMB (Tumor mutation burden), TME (Tumor microenvironment), Tregs (Regulatory T cells), UCEC (Uterine corpus endometrial carcinoma), UCS (Uterine carcinosarcoma), UVM (Uveal melanoma), VEGF (Vascular endothelial growth factor)
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