BACKGROUND: The Immunoscore method, based on the distribution of the quantification of cytotoxic and memory T cells, provides an indicator of tumor recurrence for colon cancer. However, recent evidence has suggested that immune checkpoint expression represents a surrogate measure of tumor-infiltrating T cell exhaustion, and therefore may serve as a more accurate prognostic biomarker for colon cancer. Indoleamine 2, 3-dioxygenase 1 (IDO1), a potent immunosuppressive molecule, has been strongly associated with T-cell infiltration, but it lacks universal prognostic significance among all of the cancer subtypes. Our aim was to elucidate the prognostic significance of the combination of IDO1 and CD8A expression in colon cancer. METHODS: Gene expression and clinical survival data were analyzed using The Cancer Genome Atlas (TCGA) data set and validated using NCBI Gene Expression Omnibus (NCBI-GEO) cohort. Hierarchical clustering, functional enrichment analyses, and immune infiltration analysis were applied to evaluate the distinctive immune statuses in colon cancer risk subgroups stratified by IDO1 and CD8A expression. Moreover, Multivariate Cox regression analysis and Receiver Operating Characteristic (ROC) analyses were conducted to determine the prognostic value of IDO1/CD8A stratification. The IDO1/CD8A classifier may be suitable for use in the prediction of cancer development. It was validated via an in vivo murine model. RESULTS: The stratification analysis demonstrated that the colon cancer subtype with the CD8AhighIDO1high* tumor resulted in the worst survival despite high levels of CD8 infiltrates. Its poor prognosis was associated with high levels of immune response, checkpoint genes, and Th1/IFN-γ gene signatures, regardless of CMS classification. Moreover, the IDO1/CD8A stratification was identified as an independent prognostic factor of overall survival (OS) and a useful predictive biomarker in colon cancer. In vivo data revealed the CD8AhighIDO1high group showed strong correlations with late-stage metastasis of colon carcinoma cells and upregulation of immune checkpoints. CONCLUSIONS: The findings indicate that the proposed IDO1/CD8A stratification has exact and independent prognostic implications beyond CD8 T cell alone and CMS classification. As a result, it may represent a promising tool for risk stratification in colon cancer and improve the development of immunotherapies for patients with colon cancer in the future.
BACKGROUND: The Immunoscore method, based on the distribution of the quantification of cytotoxic and memory T cells, provides an indicator of tumor recurrence for colon cancer. However, recent evidence has suggested that immune checkpoint expression represents a surrogate measure of tumor-infiltrating T cell exhaustion, and therefore may serve as a more accurate prognostic biomarker for colon cancer. Indoleamine 2, 3-dioxygenase 1 (IDO1), a potent immunosuppressive molecule, has been strongly associated with T-cell infiltration, but it lacks universal prognostic significance among all of the cancer subtypes. Our aim was to elucidate the prognostic significance of the combination of IDO1 and CD8A expression in colon cancer. METHODS: Gene expression and clinical survival data were analyzed using The Cancer Genome Atlas (TCGA) data set and validated using NCBI Gene Expression Omnibus (NCBI-GEO) cohort. Hierarchical clustering, functional enrichment analyses, and immune infiltration analysis were applied to evaluate the distinctive immune statuses in colon cancer risk subgroups stratified by IDO1 and CD8A expression. Moreover, Multivariate Cox regression analysis and Receiver Operating Characteristic (ROC) analyses were conducted to determine the prognostic value of IDO1/CD8A stratification. The IDO1/CD8A classifier may be suitable for use in the prediction of cancer development. It was validated via an in vivo murine model. RESULTS: The stratification analysis demonstrated that the colon cancer subtype with the CD8AhighIDO1high* tumor resulted in the worst survival despite high levels of CD8 infiltrates. Its poor prognosis was associated with high levels of immune response, checkpoint genes, and Th1/IFN-γ gene signatures, regardless of CMS classification. Moreover, the IDO1/CD8A stratification was identified as an independent prognostic factor of overall survival (OS) and a useful predictive biomarker in colon cancer. In vivo data revealed the CD8AhighIDO1high group showed strong correlations with late-stage metastasis of colon carcinoma cells and upregulation of immune checkpoints. CONCLUSIONS: The findings indicate that the proposed IDO1/CD8A stratification has exact and independent prognostic implications beyond CD8 T cell alone and CMS classification. As a result, it may represent a promising tool for risk stratification in colon cancer and improve the development of immunotherapies for patients with colon cancer in the future.
Authors: Christoph Reissfelder; Slava Stamova; Christina Gossmann; Marion Braun; Andreas Bonertz; Ute Walliczek; Mario Grimm; Nuh N Rahbari; Moritz Koch; Maral Saadati; Axel Benner; Markus W Büchler; Dirk Jäger; Niels Halama; Khashayarsha Khazaie; Jürgen Weitz; Philipp Beckhove Journal: J Clin Invest Date: 2014-12-22 Impact factor: 14.808
Authors: Qing Zhou; Meghan E Munger; Rachelle G Veenstra; Brenda J Weigel; Mitsuomi Hirashima; David H Munn; William J Murphy; Miyuki Azuma; Ana C Anderson; Vijay K Kuchroo; Bruce R Blazar Journal: Blood Date: 2011-03-08 Impact factor: 22.113
Authors: Tullia C Bruno; Jena D French; Kimberly R Jordan; Oscar Ramirez; Trisha R Sippel; Virginia F Borges; Bryan R Haugen; Martin D McCarter; Allen Waziri; Jill E Slansky Journal: Immunol Res Date: 2013-03 Impact factor: 2.829
Authors: Lijie Zhai; Erik Ladomersky; Kristen L Lauing; Meijing Wu; Matthew Genet; Galina Gritsina; Balázs Győrffy; Priscilla K Brastianos; David C Binder; Jeffrey A Sosman; Francis J Giles; Charles D James; Craig Horbinski; Roger Stupp; Derek A Wainwright Journal: Clin Cancer Res Date: 2017-07-27 Impact factor: 12.531
Authors: Song Cao; Kristine M Wylie; Matt A Wyczalkowski; Alla Karpova; Jessica Ley; Sam Sun; R Jay Mashl; Wen-Wei Liang; Xiaowei Wang; Kimberly Johnson; John F DiPersio; Hiram Gay; Lee Ratner; Feng Chen; Douglas R Adkins; Li Ding Journal: Commun Biol Date: 2019-03-22
Authors: Shawn D Blackburn; Haina Shin; W Nicholas Haining; Tao Zou; Creg J Workman; Antonio Polley; Michael R Betts; Gordon J Freeman; Dario A A Vignali; E John Wherry Journal: Nat Immunol Date: 2008-11-30 Impact factor: 25.606