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:BackgroundAntitumor mechanisms of CD4+ T cells remain crudely defined, and means to effectively harness CD4+ T-cell help for cancer immunotherapy are lacking. Pre-existing memory CD4+ T cells hold potential to be leveraged for this purpose. Moreover, the role of pre-existing immunity in virotherapy, particularly recombinant poliovirus immunotherapy where childhood polio vaccine specific immunity is ubiquitous, remains unclear. Here we tested the hypothesis that childhood vaccine-specific memory T cells mediate antitumor immunotherapy and contribute to the antitumor efficacy of polio virotherapy.MethodsThe impact of polio immunization on polio virotherapy, and the antitumor effects of polio and tetanus recall were tested in syngeneic murine melanoma and breast cancer models. CD8+ T-cell and B-cell knockout, CD4+ T-cell depletion, CD4+ T-cell adoptive transfer, CD40L blockade, assessments of antitumor T-cell immunity, and eosinophil depletion defined antitumor mechanisms of recall antigens. Pan-cancer transcriptome data sets and polio virotherapy clinical trial correlates were used to assess the relevance of these findings in humans.ResultsPrior vaccination against poliovirus substantially bolstered the antitumor efficacy of polio virotherapy in mice, and intratumor recall of poliovirus or tetanus immunity delayed tumor growth. Intratumor recall antigens augmented antitumor T-cell function, caused marked tumor infiltration of type 2 innate lymphoid cells and eosinophils, and decreased proportions of regulatory T cells (Tregs). Antitumor effects of recall antigens were mediated by CD4+ T cells, limited by B cells, independent of CD40L, and dependent on eosinophils and CD8+ T cells. An inverse relationship between eosinophil and Treg signatures was observed across The Cancer Genome Atlas (TCGA) cancer types, and eosinophil depletion prevented Treg reductions after polio recall. Pretreatment polio neutralizing antibody titers were higher in patients living longer, and eosinophil levels increased in the majority of patients, after polio virotherapy.ConclusionPre-existing anti-polio immunity contributes to the antitumor efficacy of polio virotherapy. This work defines cancer immunotherapy potential of childhood vaccines, reveals their utility to engage CD4+ T-cell help for antitumor CD8+ T cells, and implicates eosinophils as antitumor effectors of CD4+ T cells.

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.

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Dataset Information

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

Background

Methods

Results

Conclusion

Publications

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

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