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)To read this article in full you will need to make a payment
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Article info
Publication history
Published online: December 28, 2022
Accepted:
December 22,
2022
Received in revised form:
December 3,
2022
Received:
January 29,
2022
Publication stage
In Press Journal Pre-ProofIdentification
Copyright
© 2022 Elsevier Inc. All rights reserved.
