Significance of Expression of Immunomodulatory B7 Family Members B7-H3 and B7-H4 in Epithelial Ovarian Cancer

Thus far, ovarian cancer has had low response rates to immunotherapy despite strong evidence that the immune system is able to mount an anti-tumor response. Further investigation into the tumor microenvironment of epithelial ovarian cancer will facilitate the development of more effective immunotherapies. This thesis focuses on characterizing the tumor immune microenvironment using flow cytometry, histology, and genomic analyses. I have focused on investigating the expression patterns of B7-H3 and B7-H4, two members of the B7 family of immunomodulatory proteins as these molecules are being investigated as potential immunotherapeutic targets. In Chapter III of this thesis, it was found that B7-H3 was commonly expressed on the cell surface of tumor, stromal, and immune cells. Stromal cells expressed higher levels of B7-H3 than tumor cells, and this differential expression could be used to identify tumor and stromal cells by flow cytometry. The tumor-to-stroma ratio was calculated using differential B7-H3 expression and differences in the immune infiltrate associated with tumor-stroma ratio were assessed. A higher tumor-to-stroma ratio was associated with greater proportions of CD8+ T cells expressing high levels of PD-1, higher CD16 expression on monocytes, and higher PD-L1 expression on antigen-presenting cells. In Chapter IV of this thesis, B7-H4 expression in epithelial ovarian cancer was evaluated. Unlike B7-H3, B7-H4 expression was restricted to the tumor cell compartment and was not expressed by stromal cells. While B7-H4 was frequently expressed in the tumor cell cytoplasm, membrane-bound expression was less frequent. Genomic analyses revealed that B7-H4 expression was strongly correlated with expression of CXCL17, a monocyte chemoattractant. Further, tumors with high B7-H4 expression had higher frequencies of infiltrating APCs but did not have increased frequencies of infiltrating T or B cells. This work provides valuable information about the expression patterns of B7-H3 and B7-H4 on the tumor, stromal, and immune cells in epithelial ovarian cancer. We have performed a comprehensive analysis of the immune infiltrate in relation to expression of B7-H4 or the tumor-to-stroma ratio of tumors. Taken together, this detail of the tumor immune microenvironment provides context that can inform the potential therapeutic uses of B7-H3 and B7-H4 targeting agents in ovarian cancer.Ph.D