Abstract
Costimulatory molecules were considered to be promising and important targets in immunotherapy for various cancers. The present study was intended for generating a costimulatory molecule signature in kidney renal clear cell carcinoma (KIRC), to investigate prognostic implication, elucidate immune atlas, and predict immunotherapy response. All the KIRC samples from the TCGA were randomly divided into the training dataset and the testing dataset in the ratio of 7:3. The Cox and least absolute shrinkage and selection operator (LASSO) regression analysis were used to identify 7 key costimulatory molecules which were associated with prognosis and construct a costimulatory molecule prognostic index (CMsPI), which was validated by internal and external datasets and an independent cohort. Patients in the high-CMsPI group had high mortality. Mutation analysis showed the most common mutational genes and variant types. Immune analysis demonstrated CD8+ T cells were infiltrated at a high level in the high-CMsPI group. In combination of analysis of the immune relevant gene signature and the biomarkers of immunotherapy, we may infer there were more dysfunctional CD8+ T cells in the high-CMsPI group, and the patients of this group were less sensitive to immunotherapy. A nomogram was constructed, and the concordance index was 0.77 (95% CI: 0.74–0.79). Three key signaling pathways were identified to facilitate tumor progression. The CMsPI can be regarded as a promising biomarker for predicting individual prognosis and assessing immunotherapy response in KIRC patients.
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Data availability
The data used and analyzed during the present study are available from TCGA (https://portal.gdc.cancer.gov/), GEO (https://www.ncbi.nlm.nih.gov/geo/query/acc.cgi?acc=GSE29609), Metascape (http://metascape.org/gp/index.html#/main/step1), Estimation of STromal and Immune cells in MAlignant Tumor tissues using Expression data (ESTIMATE) (https://bioinformatics.mdanderson.org/estimate/), Estimating the Proportion of Immune and Cancer cells (EPIC) (http://epic.gfellerlab.org/), Microenvironment Cell Populations-counter (MCP-counter) (http://timer.cistrome.org/), quanTIseq (http://icbi.at/quantiseq), xCell (http://xCell.ucsf.edu/), the Cancer Immunome Atlas (TCIA) (https://tcia.at/home), Tumor Immune Dysfunction and Exclusion (TIDE) (http://tide.dfci.harvard.edu), and Gene Set Enrichment Analysis (GSEA) (https://www.gsea-msigdb.org/gsea/index.jsp).
Abbreviations
- KIRC :
-
Kidney renal clear cell carcinoma
- PD1 :
-
Programmed cell death protein 1
- CMs :
-
Costimulatory molecules
- DECMs :
-
Differentially expressed costimulatory molecules
- ICOS :
-
Inducible T cell co-stimulator
- GO :
-
Gene Ontology
- KEGG :
-
Kyoto Encyclopedia of Genes and Genomes
- CMsPI :
-
Costimulatory molecules prognostic index
- LASSO :
-
The least absolute shrinkage and selection operator
- ROC :
-
The receiver operating characteristic
- ssGSEA :
-
Single sample gene set enrichment analysis
- TIDE :
-
Tumor immune dysfunction and exclusion
- TMB :
-
Tumor mutation burden
- TIICs :
-
Tumor-infiltrating immune cells
- ESTIMATE :
-
Malignant tumor tissues using expression data
- ICIs :
-
Immune checkpoints inhibitors
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Acknowledgements
We greatly appreciate the TCGA program, GEO database, ESTIMATE database, Estimating the Proportion of Immune and Cancer cells (EPIC) database, Microenvironment Cell Populations-counter database, quanTIseq database, xCell database, the Cancer Immunome Atlas (TCIA) database and Tumor Immune Dysfunction and Exclusion (TIDE) database for providing the open-source data, and thanks for Metascape and Gene Set Enrichment Analysis (GSEA) for online analysis.
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Conception and design: GL, YJN, and GTL. Data collection: GTL, YYY, QFF, FFZ, and CNS. Data analysis and interpretation: GTL, YYY, QFF, FFZ, and CNS. Manuscript writing: GTL, YYY, QFF. Final approval of manuscript: all the authors.
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The study protocols were approved by the Ethical Committee Review Board of the Second Hospital of Tianjin Medical University (Tianjin, China). All the participants provided written informed consent.
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Lin, G., Yang, Y., Feng, Q. et al. Prognostic implication and immunotherapy response prediction of a costimulatory molecule signature in kidney renal clear cell carcinoma. Immunogenetics 74, 285–301 (2022). https://doi.org/10.1007/s00251-021-01246-1
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DOI: https://doi.org/10.1007/s00251-021-01246-1