Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancer
Abstract Background Immunostimulatory therapies targeting immune-suppressive pathways produce durable responses in advanced solid tumors. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting oxidoreductase that catalyzes the degradation of tryptophan to kynurenine. IDO induces immune tolerance by...
| Main Authors: | , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2017-10-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-017-0285-7 |
| _version_ | 1818305622387458048 |
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| author | Daniel E. Carvajal-Hausdorf Nikita Mani Vamsidhar Velcheti Kurt A. Schalper David L. Rimm |
| author_facet | Daniel E. Carvajal-Hausdorf Nikita Mani Vamsidhar Velcheti Kurt A. Schalper David L. Rimm |
| author_sort | Daniel E. Carvajal-Hausdorf |
| collection | DOAJ |
| description | Abstract Background Immunostimulatory therapies targeting immune-suppressive pathways produce durable responses in advanced solid tumors. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting oxidoreductase that catalyzes the degradation of tryptophan to kynurenine. IDO induces immune tolerance by downregulating CD8+ and effector CD4+ T cell responses. IDO1, the most active isoform, is expressed in diverse tumor types and can be targeted using small molecule inhibitors. We used an objective, in situ assay to measure IDO1 in a collection of hormone receptor-positive breast cancers (HR+ BC). Methods IDO1 protein was measured using quantitative immunofluorescence in 362 stage I-III HR+ BC represented in tissue microarrays. IDO1 levels were determined in the tumor and stroma, and stratified using median cut-point. Associations between IDO1, clinico-pathological features and CD3+, CD8+, CD20+ and FOXP3 tumor-infiltrating lymphocytes were examined using χ2 and Mann-Whitney tests. Survival was studied using Kaplan-Meier estimator and a proportional hazards model. All tests were two-sided. Results IDO1 protein was observed in 76.2% of HR+ BC. There was no association between IDO1 and major clinico-pathological characteristics. Increased IDO1 correlated with decreased CD20+ infiltration (P = 0.0004) but not with CD3+, CD8+ or FOXP3 levels. Elevated IDO1 expression was associated with worse 20-year overall survival (log-rank P = 0.02, HR = 1.39, 95% C.I.: 1.05-1.82). IDO1 scores were independently associated with outcome in multivariable analysis. Conclusions IDO1 protein is expressed in the majority of HR+ BC and is an independent negative prognostic marker. Additionally, IDO1 expression is negatively associated with tumor B-cell infiltration. Measurement of IDO1 has the potential to identify a population that might derive benefit from IDO1 blockade. |
| first_indexed | 2024-12-13T06:29:31Z |
| format | Article |
| id | doaj.art-5da7235e84ce4562856d83faaf9eb4f2 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-13T06:29:31Z |
| publishDate | 2017-10-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-5da7235e84ce4562856d83faaf9eb4f22022-12-21T23:56:38ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262017-10-01511910.1186/s40425-017-0285-7Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancerDaniel E. Carvajal-Hausdorf0Nikita Mani1Vamsidhar Velcheti2Kurt A. Schalper3David L. Rimm4Department of Pathology, Yale School of MedicineDepartment of Pathology, Yale School of MedicineSolid Tumor Oncology, Taussig Cancer Institute, Cleveland ClinicDepartment of Pathology, Yale School of MedicineDepartment of Pathology, Yale School of MedicineAbstract Background Immunostimulatory therapies targeting immune-suppressive pathways produce durable responses in advanced solid tumors. Indoleamine 2,3-dioxygenase (IDO) is the rate-limiting oxidoreductase that catalyzes the degradation of tryptophan to kynurenine. IDO induces immune tolerance by downregulating CD8+ and effector CD4+ T cell responses. IDO1, the most active isoform, is expressed in diverse tumor types and can be targeted using small molecule inhibitors. We used an objective, in situ assay to measure IDO1 in a collection of hormone receptor-positive breast cancers (HR+ BC). Methods IDO1 protein was measured using quantitative immunofluorescence in 362 stage I-III HR+ BC represented in tissue microarrays. IDO1 levels were determined in the tumor and stroma, and stratified using median cut-point. Associations between IDO1, clinico-pathological features and CD3+, CD8+, CD20+ and FOXP3 tumor-infiltrating lymphocytes were examined using χ2 and Mann-Whitney tests. Survival was studied using Kaplan-Meier estimator and a proportional hazards model. All tests were two-sided. Results IDO1 protein was observed in 76.2% of HR+ BC. There was no association between IDO1 and major clinico-pathological characteristics. Increased IDO1 correlated with decreased CD20+ infiltration (P = 0.0004) but not with CD3+, CD8+ or FOXP3 levels. Elevated IDO1 expression was associated with worse 20-year overall survival (log-rank P = 0.02, HR = 1.39, 95% C.I.: 1.05-1.82). IDO1 scores were independently associated with outcome in multivariable analysis. Conclusions IDO1 protein is expressed in the majority of HR+ BC and is an independent negative prognostic marker. Additionally, IDO1 expression is negatively associated with tumor B-cell infiltration. Measurement of IDO1 has the potential to identify a population that might derive benefit from IDO1 blockade.http://link.springer.com/article/10.1186/s40425-017-0285-7IDO1Hormone receptor-positiveSurvivalTumor-infiltrating lymphocytesQuantitative immunofluorescence |
| spellingShingle | Daniel E. Carvajal-Hausdorf Nikita Mani Vamsidhar Velcheti Kurt A. Schalper David L. Rimm Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancer Journal for ImmunoTherapy of Cancer IDO1 Hormone receptor-positive Survival Tumor-infiltrating lymphocytes Quantitative immunofluorescence |
| title | Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancer |
| title_full | Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancer |
| title_fullStr | Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancer |
| title_full_unstemmed | Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancer |
| title_short | Objective measurement and clinical significance of IDO1 protein in hormone receptor-positive breast cancer |
| title_sort | objective measurement and clinical significance of ido1 protein in hormone receptor positive breast cancer |
| topic | IDO1 Hormone receptor-positive Survival Tumor-infiltrating lymphocytes Quantitative immunofluorescence |
| url | http://link.springer.com/article/10.1186/s40425-017-0285-7 |
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