Dataset Information

Immune-related genes in tumor-specific CD4⁺ and CD8⁺ T cells in colon cancer.

ABSTRACT:

Background

Immune escape is an immunological mechanism underlying tumorigenesis, and T cells play an important role in this process. In this study, immune-related genes were evaluated in tumor-infiltrating CD4⁺ and CD8⁺ T cells in colon cancer.

Methods

ESTIMATE was used to calculate stromal and immune scores for tumor datasets downloaded from The Cancer Genome Atlas-Colon Cancer (COAD). Differentially expressed genes (DEGs) between samples with high and low stromal and immune scores were screened, followed by a functional enrichment analysis of the overlapping DEGs. The DEGs related to CD4⁺ and the CD8⁺ T cells were then screened. Predicted miRNA-mRNA and lncRNA-miRNA pairs were used to construct a competing endogenous RNA (ceRNA) network. Furthermore, chemical-gene interactions were predicted for genes in the ceRNA network. Kaplan-Meier survival curves were also plotted.

Results

In total, 83 stromal-related DEGs (5 up-regulated and 78 down-regulated) and 1270 immune-related DEGs (807 up-regulated and 293 down-regulated genes) were detected. The 79 overlapping DEGs were enriched for 39 biological process terms. Furthermore, 79 CD4⁺ T cell-related genes and 8 CD8⁺ T cell-related genes, such as ELK3, were screened. Additionally, ADAD1 and DLG3, related to CD4⁺ T cells, were significantly associated with the prognosis of patients with colon cancer. The chr22-38_28785274-29,006,793.1-miR-106a-5p-DDHD1 and chr22-38_28785274-29,006,793.1-miR-4319-GRHL1 axes obtained from CD4⁺ and CD8⁺ T cell-related ceRNAs were identified as candidates for further studies.

Conclusion

ELK3 is a candidate immune-related gene in colon cancer. The chr22-38_28785274-29,006,793.1-miR-106a-5p-DDHD1 and chr22-38_28785274-29,006,793.1-miR-4319-GRHL1 axes may be related to CD4⁺ and CD8⁺ T cell infiltration in colon cancer.

SUBMITTER: Yang X

PROVIDER: S-EPMC7310260 | biostudies-literature | 2020 Jun

REPOSITORIES: biostudies-literature

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Publications

Immune-related genes in tumor-specific CD4<sup>+</sup> and CD8<sup>+</sup> T cells in colon cancer.

Yang Xi X Wu Wei W Pan Yuefen Y Zhou Qing Q Xu Jiamin J Han Shuwen S

BMC cancer 20200622 1

<h4>Background</h4>Immune escape is an immunological mechanism underlying tumorigenesis, and T cells play an important role in this process. In this study, immune-related genes were evaluated in tumor-infiltrating CD4<sup>+</sup> and CD8<sup>+</sup> T cells in colon cancer.<h4>Methods</h4>ESTIMATE was used to calculate stromal and immune scores for tumor datasets downloaded from The Cancer Genome Atlas-Colon Cancer (COAD). Differentially expressed genes (DEGs) between samples with high and low s ...[more]

PMID: 32571262

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Project description:BACKGROUND:High-affinity tumor antigen-specific T-cell receptor (TCR) gene is required to engineer potent T cells for therapeutic treatment of cancer patients. However, discovery of suitable therapeutic TCR genes is hampered by the fact that naturally occurring tumor antigen-specific TCRs are generally of low-affinity, and artificial modification of TCRs can mediate cross-reactivity to other antigens expressed in normal tissues. Here, we discovered a naturally occurring T-cell clone which expressed high-affinity HLA-A*02:01 (A*02)-restricted TCR against NY-ESO-1 from a patient who had NY-ESO-1-expressing ovarian tumor. METHODS:A*02-restricted NY-ESO-1-specific T-cell clones were established from peripheral blood of patients who had NY-ESO-1-expressing ovarian tumors. TCR ? and ? chain genes were retrovirally transduced into polyclonally activated T cells. Phenotype and function of the parental and TCR-transduced T cells were analyzed by flow cytometry, ELISA and cytotoxicity assay. In vivo therapeutic efficacy was investigated in a xenograft model using NOD/SCID/IL-2R?-deficient (NSG) mice. RESULTS:A rare population of NY-ESO-1-specific T cells, which we named 19305DP, expressed cell surface CD4, CD8?, and CD8? but not CD56 and recognized A*02+NY-ESO-1+ cancer cell lines in a CD4- and CD8-independent manner. 19305DP showed a gene expression profile that is consistent with a mixed profile of CD4+ and CD8+ single-positive T cells. Both CD4+ and CD8+ T cells that were retrovirally transduced with 19305DP-derived TCR gene (19305DP-TCR) showed strong reactivity against A*02+NY-ESO-1+ cancer cells, whereas TCR genes from the conventional A*02-restricted NY-ESO-1-specific CD8+ single-positive T-cell clones functioned only in CD8+ T cells. Both 19305DP-TCR gene-engineered CD4+ and CD8+ T cells eliminated A*02+NY-ESO-1+ tumor xenografts in NSG mice. Finally, based on reactivity against a series of alanine-substituted peptides and a panel of normal human tissue-derived primary cells, 19305DP-TCR was predicted to have no cross-reactivity against any human non-NY-ESO-1 proteins. CONCLUSION:Together, our results indicate that the naturally occurring 19305DP-TCR derived from CD4+CD8+ double-positive ?? T cells, is a promising therapeutic TCR gene for effective and safe adoptive T-cell therapy in A*02+ patients with NY-ESO-1-expressing tumor.