Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSig
BackgroundAccumulating evidence has revealed that CD8+ T cell exhaustion (Tex) results in worse immunotherapy outcomes. However, the molecular functions and mechanisms of action of Tex in chemoresistance needed to be elucidated.MethodsThe populations of tumor-infiltrating CD8+ T cells (TILCD8Ts) in...
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Frontiers Media S.A.
2023-03-01
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| Series: | Frontiers in Immunology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1120886/full |
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| author | DQ. Cai DQ. Cai Diankui Cai Yiping Zou Xumeng Chen Zhixiang Jian Mude Shi Ye Lin Jueming Chen |
| author_facet | DQ. Cai DQ. Cai Diankui Cai Yiping Zou Xumeng Chen Zhixiang Jian Mude Shi Ye Lin Jueming Chen |
| author_sort | DQ. Cai |
| collection | DOAJ |
| description | BackgroundAccumulating evidence has revealed that CD8+ T cell exhaustion (Tex) results in worse immunotherapy outcomes. However, the molecular functions and mechanisms of action of Tex in chemoresistance needed to be elucidated.MethodsThe populations of tumor-infiltrating CD8+ T cells (TILCD8Ts) in chemoresistant and chemosensitive groups of the GSE25066 dataset were calculated using CIBERSORT. Differentially expressed genes (DEGs) between TILCD8Ts and other immune cells were explored by integrating 16 immune cell datasets downloaded from the gene expression omnibus (GEO) database. Gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, univariate and multivariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression of TILCD8T-specific upregulated genes were used to construct a chemoresistant TILCD8T signature (cr-TILCD8TSig). Clinical prognostic data, genomic alterations, chemotherapy response, and immunotherapy response were compared between the different cr-TILCD8TSig subgroups in the GSE25066 and the cancer genome atlas breast cancer (TCGA-BRCA) cohorts.ResultsA cr-TILCD8TSig with exhausted features was identified, consisting of seven genes (TCF7, RARRES3, ARL4C, ITK, CDH3, GZMB, and KLRD1), which were identified from 104 TILCD8Ts-specific DEGs. Our results showed that compared to the cr-TILCD8TSig-low subgroup, the -high subgroup had a poorer distant relapse-free survival (DRFS) in the GSE25066 cohort and worse progression-free survival (PFS) in the TCGA-BRCA cohort. Univariate and multivariate Cox regression analyses also demonstrated that cr-TILCD8TSig was an independent prognostic factor in the two independent cohorts. Furthermore, cr-TILCD8TSig-low patients benefited more from chemotherapy and immunotherapy than cr-TILCD8TSig-high patients. Besides, we found cell transmembrane signal transduction and the ECM may provide the molecular basis for resistance to antitumor agents in the cr-TILCD8Sig-high subgroup. For genomic alterations, we revealed that mutations in PIK3CA, DMD, and APOB were more common in the cr-TILCD8Sig-high subgroup than in the cr-TILCD8Sig-low subgroup. A nomogram was finally constructed with good discrimination and calibration.Conclusionscr-TILCD8TSig is a useful tool to independently predict prognosis, chemotherapy response, and immunotherapy outcomes in patients with breast cancer. |
| first_indexed | 2024-04-10T05:44:22Z |
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| language | English |
| last_indexed | 2024-04-10T05:44:22Z |
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| spelling | doaj.art-88321b892a3049b8a5c1602cbc6da5d62023-03-06T05:13:54ZengFrontiers Media S.A.Frontiers in Immunology1664-32242023-03-011410.3389/fimmu.2023.11208861120886Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSigDQ. Cai0DQ. Cai1Diankui Cai2Yiping Zou3Xumeng Chen4Zhixiang Jian5Mude Shi6Ye Lin7Jueming Chen8Department of General Surgery, Sun Yat-Sen Memorial Hospital, Guangzhou, ChinaDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, ChinaDepartment of General Surgery, Sun Yat-Sen Memorial Hospital, Guangzhou, ChinaDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, ChinaDepartment of Pharmacology, School of Pharmaceutical Sciences, Hunan University of Chinese Medicine, Changsha, ChinaDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, ChinaGuangdong ACXEL Micro & Nano Tech Co., Ltd, Foshan, ChinaDepartment of General Surgery, Guangdong Provincial People’s Hospital, Guangdong Academy of Medical Sciences, Guangzhou, Guangdong Province, ChinaMedical College of South China University of Technology, Guangzhou, ChinaBackgroundAccumulating evidence has revealed that CD8+ T cell exhaustion (Tex) results in worse immunotherapy outcomes. However, the molecular functions and mechanisms of action of Tex in chemoresistance needed to be elucidated.MethodsThe populations of tumor-infiltrating CD8+ T cells (TILCD8Ts) in chemoresistant and chemosensitive groups of the GSE25066 dataset were calculated using CIBERSORT. Differentially expressed genes (DEGs) between TILCD8Ts and other immune cells were explored by integrating 16 immune cell datasets downloaded from the gene expression omnibus (GEO) database. Gene ontology (GO)/Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment, univariate and multivariate Cox regression, and least absolute shrinkage and selection operator (LASSO) regression of TILCD8T-specific upregulated genes were used to construct a chemoresistant TILCD8T signature (cr-TILCD8TSig). Clinical prognostic data, genomic alterations, chemotherapy response, and immunotherapy response were compared between the different cr-TILCD8TSig subgroups in the GSE25066 and the cancer genome atlas breast cancer (TCGA-BRCA) cohorts.ResultsA cr-TILCD8TSig with exhausted features was identified, consisting of seven genes (TCF7, RARRES3, ARL4C, ITK, CDH3, GZMB, and KLRD1), which were identified from 104 TILCD8Ts-specific DEGs. Our results showed that compared to the cr-TILCD8TSig-low subgroup, the -high subgroup had a poorer distant relapse-free survival (DRFS) in the GSE25066 cohort and worse progression-free survival (PFS) in the TCGA-BRCA cohort. Univariate and multivariate Cox regression analyses also demonstrated that cr-TILCD8TSig was an independent prognostic factor in the two independent cohorts. Furthermore, cr-TILCD8TSig-low patients benefited more from chemotherapy and immunotherapy than cr-TILCD8TSig-high patients. Besides, we found cell transmembrane signal transduction and the ECM may provide the molecular basis for resistance to antitumor agents in the cr-TILCD8Sig-high subgroup. For genomic alterations, we revealed that mutations in PIK3CA, DMD, and APOB were more common in the cr-TILCD8Sig-high subgroup than in the cr-TILCD8Sig-low subgroup. A nomogram was finally constructed with good discrimination and calibration.Conclusionscr-TILCD8TSig is a useful tool to independently predict prognosis, chemotherapy response, and immunotherapy outcomes in patients with breast cancer.https://www.frontiersin.org/articles/10.3389/fimmu.2023.1120886/fullprognosischemoresistanceimmunotherapysignaturetumor-infiltrating CD8+ T cell |
| spellingShingle | DQ. Cai DQ. Cai Diankui Cai Yiping Zou Xumeng Chen Zhixiang Jian Mude Shi Ye Lin Jueming Chen Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSig Frontiers in Immunology prognosis chemoresistance immunotherapy signature tumor-infiltrating CD8+ T cell |
| title | Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSig |
| title_full | Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSig |
| title_fullStr | Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSig |
| title_full_unstemmed | Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSig |
| title_short | Construction and validation of chemoresistance-associated tumor- infiltrating exhausted-like CD8+ T cell signature in breast cancer: cr-TILCD8TSig |
| title_sort | construction and validation of chemoresistance associated tumor infiltrating exhausted like cd8 t cell signature in breast cancer cr tilcd8tsig |
| topic | prognosis chemoresistance immunotherapy signature tumor-infiltrating CD8+ T cell |
| url | https://www.frontiersin.org/articles/10.3389/fimmu.2023.1120886/full |
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