High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation
Abstract Background B7-H3 and B7-H4 are highly expressed by many human malignancies making them attractive immunotherapeutic targets. However, their expression patterns and immune contexts in epithelial ovarian cancer have not been well characterized. Methods We used flow cytometry, immunohistochemi...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
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BMJ Publishing Group
2019-12-01
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| Series: | Journal for ImmunoTherapy of Cancer |
| Subjects: | |
| Online Access: | http://link.springer.com/article/10.1186/s40425-019-0816-5 |
| _version_ | 1818883817955393536 |
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| author | Heather L. MacGregor Azin Sayad Andrew Elia Ben X. Wang Sarah Rachel Katz Patricia A. Shaw Blaise A. Clarke Sarah Q. Crome Celine Robert-Tissot Marcus Q. Bernardini Linh T. Nguyen Pamela S. Ohashi |
| author_facet | Heather L. MacGregor Azin Sayad Andrew Elia Ben X. Wang Sarah Rachel Katz Patricia A. Shaw Blaise A. Clarke Sarah Q. Crome Celine Robert-Tissot Marcus Q. Bernardini Linh T. Nguyen Pamela S. Ohashi |
| author_sort | Heather L. MacGregor |
| collection | DOAJ |
| description | Abstract Background B7-H3 and B7-H4 are highly expressed by many human malignancies making them attractive immunotherapeutic targets. However, their expression patterns and immune contexts in epithelial ovarian cancer have not been well characterized. Methods We used flow cytometry, immunohistochemistry, and genomic analyses to determine the patterns of B7-H3, B7-H4, and PD-L1 expression by tumor, stromal, and immune cells in the ovarian tumor microenvironment (TME). We analyzed immune cell frequency and expression of PD-1, TIM3, LAG3, ICOS, TIA-1, granzyme B, 2B4, CD107a, and GITR on T cells; CD20, CD22, IgD, BTLA, and CD27 on B cells; CD16 on monocytes; and B7-H3, B7-H4, PD-L1, PD-L2, ICOSL, CD40, CD86, and CLEC9a on antigen-presenting cells by flow cytometry. We determined intratumoral cellular location of immune cells using immunohistochemistry. We compared differences in immune infiltration in tumors with low or high tumor-to-stroma ratio and in tumors from the same or unrelated patients. Results On non-immune cells, B7-H4 expression was restricted to tumor cells whereas B7-H3 was expressed by both tumor and stromal cells. Stromal cells of the ovarian TME expressed high levels of B7-H3 compared to tumor cells. We used this differential expression to assess the tumor-to-stroma ratio of ovarian tumors and found that high tumor-to-stroma ratio was associated with increased expression of CD16 by monocytes, increased frequencies of PD-1high CD8+ T cells, increased PD-L1 expression by APCs, and decreased CLEC9a expression by APCs. We found that expression of PD-L1 or CD86 on APCs and the proportion of PD-1high CD4+ T cells were strongly correlated on immune cells from tumors within the same patient, whereas expression of CD40 and ICOSL on APCs and the proportion of PD-1high CD8+ T cells were not. Conclusions This study provides insight into the expression patterns of B7-H3 and B7-H4 in the ovarian TME. Further, we demonstrate an association between the tumor-to-stroma ratio and the phenotype of tumor-infiltrating immune cells. We also find that some but not all immune parameters show consistency between peritoneal metastatic sites. These data have implications for the design of immunotherapies targeting these B7 molecules in epithelial ovarian cancer. |
| first_indexed | 2024-12-19T15:39:41Z |
| format | Article |
| id | doaj.art-94955eb75206441b879db80277b112a6 |
| institution | Directory Open Access Journal |
| issn | 2051-1426 |
| language | English |
| last_indexed | 2024-12-19T15:39:41Z |
| publishDate | 2019-12-01 |
| publisher | BMJ Publishing Group |
| record_format | Article |
| series | Journal for ImmunoTherapy of Cancer |
| spelling | doaj.art-94955eb75206441b879db80277b112a62022-12-21T20:15:30ZengBMJ Publishing GroupJournal for ImmunoTherapy of Cancer2051-14262019-12-017111710.1186/s40425-019-0816-5High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activationHeather L. MacGregor0Azin Sayad1Andrew Elia2Ben X. Wang3Sarah Rachel Katz4Patricia A. Shaw5Blaise A. Clarke6Sarah Q. Crome7Celine Robert-Tissot8Marcus Q. Bernardini9Linh T. Nguyen10Pamela S. Ohashi11Department of Immunology, University of TorontoPrincess Margaret Cancer Centre, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkDivision of Gynecologic Oncology, University Health NetworkDepartment of Laboratory Medicine and Pathobiology, University Health Network, University of TorontoDepartment of Laboratory Medicine and Pathobiology, University Health Network, University of TorontoDepartment of Immunology, University of TorontoPrincess Margaret Cancer Centre, University Health NetworkDivision of Gynecologic Oncology, University Health NetworkPrincess Margaret Cancer Centre, University Health NetworkDepartment of Immunology, University of TorontoAbstract Background B7-H3 and B7-H4 are highly expressed by many human malignancies making them attractive immunotherapeutic targets. However, their expression patterns and immune contexts in epithelial ovarian cancer have not been well characterized. Methods We used flow cytometry, immunohistochemistry, and genomic analyses to determine the patterns of B7-H3, B7-H4, and PD-L1 expression by tumor, stromal, and immune cells in the ovarian tumor microenvironment (TME). We analyzed immune cell frequency and expression of PD-1, TIM3, LAG3, ICOS, TIA-1, granzyme B, 2B4, CD107a, and GITR on T cells; CD20, CD22, IgD, BTLA, and CD27 on B cells; CD16 on monocytes; and B7-H3, B7-H4, PD-L1, PD-L2, ICOSL, CD40, CD86, and CLEC9a on antigen-presenting cells by flow cytometry. We determined intratumoral cellular location of immune cells using immunohistochemistry. We compared differences in immune infiltration in tumors with low or high tumor-to-stroma ratio and in tumors from the same or unrelated patients. Results On non-immune cells, B7-H4 expression was restricted to tumor cells whereas B7-H3 was expressed by both tumor and stromal cells. Stromal cells of the ovarian TME expressed high levels of B7-H3 compared to tumor cells. We used this differential expression to assess the tumor-to-stroma ratio of ovarian tumors and found that high tumor-to-stroma ratio was associated with increased expression of CD16 by monocytes, increased frequencies of PD-1high CD8+ T cells, increased PD-L1 expression by APCs, and decreased CLEC9a expression by APCs. We found that expression of PD-L1 or CD86 on APCs and the proportion of PD-1high CD4+ T cells were strongly correlated on immune cells from tumors within the same patient, whereas expression of CD40 and ICOSL on APCs and the proportion of PD-1high CD8+ T cells were not. Conclusions This study provides insight into the expression patterns of B7-H3 and B7-H4 in the ovarian TME. Further, we demonstrate an association between the tumor-to-stroma ratio and the phenotype of tumor-infiltrating immune cells. We also find that some but not all immune parameters show consistency between peritoneal metastatic sites. These data have implications for the design of immunotherapies targeting these B7 molecules in epithelial ovarian cancer.http://link.springer.com/article/10.1186/s40425-019-0816-5B7-H4B7-H3B7 familyEpithelial ovarian cancerTumor microenvironmentIntrapatient variability, immune heterogeneity |
| spellingShingle | Heather L. MacGregor Azin Sayad Andrew Elia Ben X. Wang Sarah Rachel Katz Patricia A. Shaw Blaise A. Clarke Sarah Q. Crome Celine Robert-Tissot Marcus Q. Bernardini Linh T. Nguyen Pamela S. Ohashi High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation Journal for ImmunoTherapy of Cancer B7-H4 B7-H3 B7 family Epithelial ovarian cancer Tumor microenvironment Intrapatient variability, immune heterogeneity |
| title | High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation |
| title_full | High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation |
| title_fullStr | High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation |
| title_full_unstemmed | High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation |
| title_short | High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation |
| title_sort | high expression of b7 h3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation |
| topic | B7-H4 B7-H3 B7 family Epithelial ovarian cancer Tumor microenvironment Intrapatient variability, immune heterogeneity |
| url | http://link.springer.com/article/10.1186/s40425-019-0816-5 |
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