Multi‐omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour‐immune dynamics in colorectal cancer
Abstract Background Colorectal cancer (CRC) ranks among the most prevalent malignant tumours of the digestive system globally and is associated with unfavourable survival outcomes. The exhaustion of CD8⁺ T cells serves a crucial role in facilitating tumour immune escape. Yet, the dynamic evolution o...
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2025-08-01
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| Series: | Clinical and Translational Medicine |
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| Online Access: | https://doi.org/10.1002/ctm2.70425 |
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| author | Tengfei Jia Yingxi Guo Xin meng Cheng Zeyang Zhou Xiaojiang Xu Hebin Liu Xiaodong Yang |
| author_facet | Tengfei Jia Yingxi Guo Xin meng Cheng Zeyang Zhou Xiaojiang Xu Hebin Liu Xiaodong Yang |
| author_sort | Tengfei Jia |
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| description | Abstract Background Colorectal cancer (CRC) ranks among the most prevalent malignant tumours of the digestive system globally and is associated with unfavourable survival outcomes. The exhaustion of CD8⁺ T cells serves a crucial role in facilitating tumour immune escape. Yet, the dynamic evolution of CD8⁺ T cell exhaustion and its impact on clinical prognosis across TNM (tumour‐node‐metastasis) stages in CRC remains incompletely characterized. Methods Tumour and adjacent tissues (20 samples total) from 6 CRC patients spanning diverse TNM stages were analyzed using integrated single‐cell transcriptomic profiling (scRNA‐seq), single‐cell T cell receptor/B cell receptor sequencing (scVDJ‐seq), and spatial transcriptomics. T cell exhaustion markers, immune clonality, gene expression profiles, and the spatial distribution of both tumour cells and immune cells were systematically profiled. Functional enrichment and intercellular communication analyses were conducted. Key findings were validated using immunofluorescence and public datasets. Results Our results illustrate how advancing TNM stages in CRC shape CD8⁺ T cell exhaustion through divergent TNFRSF18/CXCL13 dynamics and ribosomal stemness. TNFRSF18 expression was notably higher in T cells infiltrating tumour tissues relative to their counterparts in adjacent non‐tumorous areas, with high‐expressing CD8⁺ T cells exhibiting marked exhaustion features. During CRC progression, TNM‐stage‐driven remodelling of the tumour microenvironment (TME) induced progressive CD8⁺ T cell exhaustion marked by declining TNFRSF18 and rising CXCL13 expression in tumour‐infiltrating T cells elevation of both markers in the tumour compared with adjacent tissues. Moreover, we show that tumour cells displayed elevated expression of stemness‐associated ribosomal genes (RPS7, RPL8, RPL30), peaking at stage T4, which correlated with poor prognosis and immune escape. Conclusions This integrative multi‐omics study uncovers CD8⁺ T cell exhaustion dynamics and ribosomal stemness‐mediated immune evasion across CRC progression. CXCL13, TNFRSF18, and ribosomal proteins (RPS7/RPL8/RPL30) are identified as novel biomarkers with direct prognostic value and therapeutic relevance, providing therapeutic targets for precision immunotherapy in CRC. Key points Multi‐omics analysis reveals dynamic CD8+ T cell exhaustion patterns across CRC samples with different TNM stages. TNFRSF18 is highly expressed in exhausted tumour‐infiltrating CD8+ T cells and declines with disease progression. Ribosomal stemness in tumour cells promotes immune evasion by impairing TNF‐mediated CD8+ T cell function. |
| format | Article |
| id | doaj-art-d6dbd9ad6edd434898fcc9e7f8ca8c43 |
| institution | Kabale University |
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| publishDate | 2025-08-01 |
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| spelling | doaj-art-d6dbd9ad6edd434898fcc9e7f8ca8c432025-08-25T18:28:44ZengWileyClinical and Translational Medicine2001-13262025-08-01158n/an/a10.1002/ctm2.70425Multi‐omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour‐immune dynamics in colorectal cancerTengfei Jia0Yingxi Guo1Xin meng Cheng2Zeyang Zhou3Xiaojiang Xu4Hebin Liu5Xiaodong Yang6Institutes of Biology and Medical Sciences Soochow University Suzhou ChinaInstitutes of Biology and Medical Sciences Soochow University Suzhou ChinaDepartment of Gastrointestinal Surgery The Second Affiliated Hospital of Soochow University Suzhou ChinaDepartment of Gastrointestinal Surgery The Second Affiliated Hospital of Soochow University Suzhou ChinaTulane University School of MedicineNew Orleans Louisiana USAInstitutes of Biology and Medical Sciences Soochow University Suzhou ChinaDepartment of Gastrointestinal Surgery The Second Affiliated Hospital of Soochow University Suzhou ChinaAbstract Background Colorectal cancer (CRC) ranks among the most prevalent malignant tumours of the digestive system globally and is associated with unfavourable survival outcomes. The exhaustion of CD8⁺ T cells serves a crucial role in facilitating tumour immune escape. Yet, the dynamic evolution of CD8⁺ T cell exhaustion and its impact on clinical prognosis across TNM (tumour‐node‐metastasis) stages in CRC remains incompletely characterized. Methods Tumour and adjacent tissues (20 samples total) from 6 CRC patients spanning diverse TNM stages were analyzed using integrated single‐cell transcriptomic profiling (scRNA‐seq), single‐cell T cell receptor/B cell receptor sequencing (scVDJ‐seq), and spatial transcriptomics. T cell exhaustion markers, immune clonality, gene expression profiles, and the spatial distribution of both tumour cells and immune cells were systematically profiled. Functional enrichment and intercellular communication analyses were conducted. Key findings were validated using immunofluorescence and public datasets. Results Our results illustrate how advancing TNM stages in CRC shape CD8⁺ T cell exhaustion through divergent TNFRSF18/CXCL13 dynamics and ribosomal stemness. TNFRSF18 expression was notably higher in T cells infiltrating tumour tissues relative to their counterparts in adjacent non‐tumorous areas, with high‐expressing CD8⁺ T cells exhibiting marked exhaustion features. During CRC progression, TNM‐stage‐driven remodelling of the tumour microenvironment (TME) induced progressive CD8⁺ T cell exhaustion marked by declining TNFRSF18 and rising CXCL13 expression in tumour‐infiltrating T cells elevation of both markers in the tumour compared with adjacent tissues. Moreover, we show that tumour cells displayed elevated expression of stemness‐associated ribosomal genes (RPS7, RPL8, RPL30), peaking at stage T4, which correlated with poor prognosis and immune escape. Conclusions This integrative multi‐omics study uncovers CD8⁺ T cell exhaustion dynamics and ribosomal stemness‐mediated immune evasion across CRC progression. CXCL13, TNFRSF18, and ribosomal proteins (RPS7/RPL8/RPL30) are identified as novel biomarkers with direct prognostic value and therapeutic relevance, providing therapeutic targets for precision immunotherapy in CRC. Key points Multi‐omics analysis reveals dynamic CD8+ T cell exhaustion patterns across CRC samples with different TNM stages. TNFRSF18 is highly expressed in exhausted tumour‐infiltrating CD8+ T cells and declines with disease progression. Ribosomal stemness in tumour cells promotes immune evasion by impairing TNF‐mediated CD8+ T cell function.https://doi.org/10.1002/ctm2.70425colorectal cancersinglecell RNA sequencingspatial transcriptomicsT cell exhaustionTNFRSF18 (GITR)TNM stage |
| spellingShingle | Tengfei Jia Yingxi Guo Xin meng Cheng Zeyang Zhou Xiaojiang Xu Hebin Liu Xiaodong Yang Multi‐omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour‐immune dynamics in colorectal cancer Clinical and Translational Medicine colorectal cancer singlecell RNA sequencing spatial transcriptomics T cell exhaustion TNFRSF18 (GITR) TNM stage |
| title | Multi‐omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour‐immune dynamics in colorectal cancer |
| title_full | Multi‐omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour‐immune dynamics in colorectal cancer |
| title_fullStr | Multi‐omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour‐immune dynamics in colorectal cancer |
| title_full_unstemmed | Multi‐omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour‐immune dynamics in colorectal cancer |
| title_short | Multi‐omics profiling identifies TNFRSF18 as a novel marker of exhausted CD8⁺ T cells and reveals tumour‐immune dynamics in colorectal cancer |
| title_sort | multi omics profiling identifies tnfrsf18 as a novel marker of exhausted cd8⁺ t cells and reveals tumour immune dynamics in colorectal cancer |
| topic | colorectal cancer singlecell RNA sequencing spatial transcriptomics T cell exhaustion TNFRSF18 (GITR) TNM stage |
| url | https://doi.org/10.1002/ctm2.70425 |
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