CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer
Abstract Unlike other histological types of epithelial ovarian carcinoma, clear cell ovarian carcinoma (CCOC) has poor response to therapy. In many other carcinomas, expression of the hypoxia-related enzyme Carbonic anhydrase IX (CAIX) by cancer cells is associated with poor prognosis, while the pre...
| Main Authors: | , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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Nature Portfolio
2023-04-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-023-30655-3 |
| _version_ | 1797841016191975424 |
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| author | Nancy Guo Aijun Yang Fabiha Binte Farooq Shreena Kalaria Elena Moss Lindsay DeVorkin Mary Lesperance François Bénard Don Wilson Anna V. Tinker Farouk S. Nathoo Phineas T. Hamilton Julian J. Lum |
| author_facet | Nancy Guo Aijun Yang Fabiha Binte Farooq Shreena Kalaria Elena Moss Lindsay DeVorkin Mary Lesperance François Bénard Don Wilson Anna V. Tinker Farouk S. Nathoo Phineas T. Hamilton Julian J. Lum |
| author_sort | Nancy Guo |
| collection | DOAJ |
| description | Abstract Unlike other histological types of epithelial ovarian carcinoma, clear cell ovarian carcinoma (CCOC) has poor response to therapy. In many other carcinomas, expression of the hypoxia-related enzyme Carbonic anhydrase IX (CAIX) by cancer cells is associated with poor prognosis, while the presence of CD8 + tumor-infiltrating lymphocytes (TIL) is positively prognostic. We employed [18F]EF5-PET/CT imaging, transcriptome profiling, and spatially-resolved histological analysis to evaluate relationships between CAIX, CD8, and survival in CCOC. Tissue microarrays (TMAs) were evaluated for 218 cases in the Canadian COEUR study. Non-spatial relationships between CAIX and CD8 were investigated using Spearman rank correlation, negative binomial regression and gene set enrichment analysis. Spatial relationships at the cell level were investigated using the cross K-function. Survival analysis was used to assess the relationship of CAIX and CD8 with patient survival for 154 cases. CD8 + T cell infiltration positively predicted survival with estimated hazard ratio 0.974 (95% CI 0.950, 1000). The negative binomial regression analysis found a strong TMA effect (p-value < 0.0001). It also indicated a negative association between CD8 and CAIX overall (p-value = 0.0171) and in stroma (p-value = 0.0050) but not in tumor (p-value = 0.173). Examination of the spatial association between the locations of CD8 + T cells and CAIX cells found a significant amount of heterogeneity in the first TMA, while in the second TMA there was a clear signal indicating negative spatial association in stromal regions. These results suggest that hypoxia may contribute to immune exclusion, primarily mediated by effects in stroma. |
| first_indexed | 2024-04-09T16:24:03Z |
| format | Article |
| id | doaj.art-95ede8de1ca14914bdce66a61cd611f5 |
| institution | Directory Open Access Journal |
| issn | 2045-2322 |
| language | English |
| last_indexed | 2024-04-09T16:24:03Z |
| publishDate | 2023-04-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Scientific Reports |
| spelling | doaj.art-95ede8de1ca14914bdce66a61cd611f52023-04-23T11:18:11ZengNature PortfolioScientific Reports2045-23222023-04-0113111010.1038/s41598-023-30655-3CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancerNancy Guo0Aijun Yang1Fabiha Binte Farooq2Shreena Kalaria3Elena Moss4Lindsay DeVorkin5Mary Lesperance6François Bénard7Don Wilson8Anna V. Tinker9Farouk S. Nathoo10Phineas T. Hamilton11Julian J. Lum12Department of Mathematics and Statistics, University of VictoriaDepartment of Mathematics and Statistics, University of VictoriaDepartment of Economics, University of VictoriaTrev and Joyce Deeley Research Centre, BC Cancer, VictoriaTrev and Joyce Deeley Research Centre, BC Cancer, VictoriaTrev and Joyce Deeley Research Centre, BC Cancer, VictoriaDepartment of Mathematics and Statistics, University of VictoriaDepartment of Radiology, University of British ColumbiaFunctional Imaging, BC Cancer VancouverMedical Oncology, BC Cancer VancouverDepartment of Mathematics and Statistics, University of VictoriaTrev and Joyce Deeley Research Centre, BC Cancer, VictoriaTrev and Joyce Deeley Research Centre, BC Cancer, VictoriaAbstract Unlike other histological types of epithelial ovarian carcinoma, clear cell ovarian carcinoma (CCOC) has poor response to therapy. In many other carcinomas, expression of the hypoxia-related enzyme Carbonic anhydrase IX (CAIX) by cancer cells is associated with poor prognosis, while the presence of CD8 + tumor-infiltrating lymphocytes (TIL) is positively prognostic. We employed [18F]EF5-PET/CT imaging, transcriptome profiling, and spatially-resolved histological analysis to evaluate relationships between CAIX, CD8, and survival in CCOC. Tissue microarrays (TMAs) were evaluated for 218 cases in the Canadian COEUR study. Non-spatial relationships between CAIX and CD8 were investigated using Spearman rank correlation, negative binomial regression and gene set enrichment analysis. Spatial relationships at the cell level were investigated using the cross K-function. Survival analysis was used to assess the relationship of CAIX and CD8 with patient survival for 154 cases. CD8 + T cell infiltration positively predicted survival with estimated hazard ratio 0.974 (95% CI 0.950, 1000). The negative binomial regression analysis found a strong TMA effect (p-value < 0.0001). It also indicated a negative association between CD8 and CAIX overall (p-value = 0.0171) and in stroma (p-value = 0.0050) but not in tumor (p-value = 0.173). Examination of the spatial association between the locations of CD8 + T cells and CAIX cells found a significant amount of heterogeneity in the first TMA, while in the second TMA there was a clear signal indicating negative spatial association in stromal regions. These results suggest that hypoxia may contribute to immune exclusion, primarily mediated by effects in stroma.https://doi.org/10.1038/s41598-023-30655-3 |
| spellingShingle | Nancy Guo Aijun Yang Fabiha Binte Farooq Shreena Kalaria Elena Moss Lindsay DeVorkin Mary Lesperance François Bénard Don Wilson Anna V. Tinker Farouk S. Nathoo Phineas T. Hamilton Julian J. Lum CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer Scientific Reports |
| title | CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer |
| title_full | CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer |
| title_fullStr | CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer |
| title_full_unstemmed | CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer |
| title_short | CD8 + T cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer |
| title_sort | cd8 t cell infiltration is associated with improved survival and negatively correlates with hypoxia in clear cell ovarian cancer |
| url | https://doi.org/10.1038/s41598-023-30655-3 |
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