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Background <p>CD3D encodes the delta chain of the CD3 complex and is a core component of T-cell receptor (TCR) signaling, playing an essential role in T-cell activation and immune responses. While CD3D is well recognized as a T-cell-associated molecule, its expression patterns, prognostic relevance, and association with the tumor immune microenvironment across different cancer types have not been systematically evaluated.</p> Methods <p>Publicly available pan-cancer datasets were obtained from the University of California Santa Cruz (UCSC) Xena platform, including data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) projects. CD3D expression profiles were analyzed across multiple tumor types, and their associations with clinical outcomes were evaluated using survival analyses. Correlations between CD3D expression and immune cell infiltration were assessed using multiple established computational algorithms, along with immune-related gene expression, immune checkpoint markers, and indicators of genomic heterogeneity. Functional enrichment and protein-protein interaction analyses were conducted to explore CD3D-associated biological pathways. Furthermore, multiplex immunohistochemistry (mIHC) was performed on tissue microarrays (TMAs) containing 170 endometrial cancer (EC) cases to spatially validate the protein expression of CD3D, CD8, and PD-L1 in intratumoral and stromal regions.</p> Results <p>CD3D expression exhibited substantial heterogeneity across cancer types and was associated with clinical stage and patient prognosis in a cancer-type-dependent manner. After Benjamini-Hochberg FDR correction, CD3D expression remained significantly different between tumor and normal tissues in 13 of 20 unpaired tumor-normal comparisons and in 7 of 20 paired tumor-normal comparisons. Elevated CD3D expression was correlated with increased immune cell infiltration, higher immune and stromal scores, and expression of immune regulatory molecules and immune checkpoints in a cancer-type-dependent manner. Clinical validation via mIHC in the EC cohort revealed that intratumoral CD3D high expression was associated with younger age, earlier FIGO stage, and LVSI-negative status, whereas stromal CD3D expression was not significantly associated with the analyzed clinicopathological variables. Intratumoral CD3D expression was associated with OS in univariate analysis but was attenuated after multivariate adjustment; intratumoral CD3D+CD8 + T-cell density remained independently associated with improved OS after multivariate adjustment.</p> Conclusion <p>CD3D is a T-cell-associated marker that reflects T-cell infiltration and an immune-inflamed tumor microenvironment, with prognostic relevance that depends on cancer type, spatial localization, and cytotoxic T-cell context.</p>

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Pan-cancer analysis and spatial validation in endometrial cancer reveal CD3D as a prognostic and immunological biomarker

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年8月5日

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  • Qian Lu,
  • Xinrong Ji,
  • Haifeng Shan,
  • Tianqi Wang,
  • Xiaoyan Ge,
  • Weihong Gu,
  • Jieying Li

摘要

Background

CD3D encodes the delta chain of the CD3 complex and is a core component of T-cell receptor (TCR) signaling, playing an essential role in T-cell activation and immune responses. While CD3D is well recognized as a T-cell-associated molecule, its expression patterns, prognostic relevance, and association with the tumor immune microenvironment across different cancer types have not been systematically evaluated.

Methods

Publicly available pan-cancer datasets were obtained from the University of California Santa Cruz (UCSC) Xena platform, including data from The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) projects. CD3D expression profiles were analyzed across multiple tumor types, and their associations with clinical outcomes were evaluated using survival analyses. Correlations between CD3D expression and immune cell infiltration were assessed using multiple established computational algorithms, along with immune-related gene expression, immune checkpoint markers, and indicators of genomic heterogeneity. Functional enrichment and protein-protein interaction analyses were conducted to explore CD3D-associated biological pathways. Furthermore, multiplex immunohistochemistry (mIHC) was performed on tissue microarrays (TMAs) containing 170 endometrial cancer (EC) cases to spatially validate the protein expression of CD3D, CD8, and PD-L1 in intratumoral and stromal regions.

Results

CD3D expression exhibited substantial heterogeneity across cancer types and was associated with clinical stage and patient prognosis in a cancer-type-dependent manner. After Benjamini-Hochberg FDR correction, CD3D expression remained significantly different between tumor and normal tissues in 13 of 20 unpaired tumor-normal comparisons and in 7 of 20 paired tumor-normal comparisons. Elevated CD3D expression was correlated with increased immune cell infiltration, higher immune and stromal scores, and expression of immune regulatory molecules and immune checkpoints in a cancer-type-dependent manner. Clinical validation via mIHC in the EC cohort revealed that intratumoral CD3D high expression was associated with younger age, earlier FIGO stage, and LVSI-negative status, whereas stromal CD3D expression was not significantly associated with the analyzed clinicopathological variables. Intratumoral CD3D expression was associated with OS in univariate analysis but was attenuated after multivariate adjustment; intratumoral CD3D+CD8 + T-cell density remained independently associated with improved OS after multivariate adjustment.

Conclusion

CD3D is a T-cell-associated marker that reflects T-cell infiltration and an immune-inflamed tumor microenvironment, with prognostic relevance that depends on cancer type, spatial localization, and cytotoxic T-cell context.