Date of Graduation
8-2016
Document Type
Thesis (MS)
Program Affiliation
Biomedical Sciences
Degree Name
Masters of Science (MS)
Advisor/Committee Chair
Karen Lu
Committee Member
Melinda Yates
Committee Member
Samuel Mok
Committee Member
Russell Broaddus
Committee Member
Padmanee Sharma
Abstract
Limited treatment options are available for patients with advanced and recurrent endometrial cancer (EC) should standard chemotherapy fail. Recent studies in other tumor types have shown that tumors with high microsatellite instability (MSI-H) have increased immunogenicity and response to immunotherapy treatments compared to microsatellite stable (MSS) tumors. Patients with MSI-H EC may also benefit from these therapies; however, the tumor immune microenvironment in MSI-H EC has not yet been well described.
In order to evaluate the immune microenvironment of MSI-H EC, multiple approaches were used, including analysis of large publically available datasets and detailed characterization of patient tumor samples. Uterine cancer data from The Cancer Genome Atlas (TCGA) was used to study immune-related gene expression in MSI-H EC compared to MSS EC at both the individual gene and pathway level. Fluorescent multiplexing immunohistochemistry (IHC) was used to evaluate differences in immune cell populations using tumor specimens from these two groups followed by automated multispectral imaging and analysis to visualize and quantify staining in the tumor epithelial and stromal compartments. Nonparametric Mann-Whitney test was used to determine statistical significance (p value
Overall, MSI-H EC demonstrated increased immune activation compared to MSS EC. Using TCGA data, MSI-H (n=118) EC showed overall activation of the granzyme B signaling pathway compared to MSS (n=160) EC (p +cells (114.9 cells/mm2 vs 75.8 cells/mm2; p2 vs 28.0 cells/mm2; p+ cells (291.6 cells/mm2 vs 240.5 cells/mm2; p+ and activated cytotoxic T cells was also increased in the tumor epithelial compartment of MSI-H compared to MSS ECs. There was no difference in the other markers evaluated.
In conclusion, the immune microenvironment differs in MSI-H ECs with increased tumor immunogenicity compared to MSS tumors. Elevated PD-L1 expression also suggests immune response inhibition in these tumors, and patients with this subset of tumors are likely candidates for immune checkpoint blocking agents.
Keywords
endometrial cancer, immunotherapy, immune microenvironment, microsatellite instability