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High expression of B7-H3 on stromal cells defines tumor and stromal compartments in epithelial ovarian cancer and is associated with limited immune activation. | LitMetric

AI Article Synopsis

  • B7-H3 and B7-H4 are promising targets for immunotherapy in epithelial ovarian cancer, but their specific expression patterns within the tumor microenvironment remain unclear.
  • The study employed techniques like flow cytometry and immunohistochemistry to analyze the expression of these molecules alongside various immune cell markers, revealing that B7-H4 is mainly found in tumor cells, while B7-H3 is present in both tumor and stromal cells.
  • High tumor-to-stroma ratios correlated with changes in immune cell characteristics, suggesting a complex relationship between B7-H3/B7-H4 expression and immune response in ovarian cancer, which could influence future therapeutic strategies.

Article 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-1 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-1 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-1 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.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC6937725PMC
http://dx.doi.org/10.1186/s40425-019-0816-5DOI Listing

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