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

Available for download on Monday, August 14, 2017

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Oncology Commons

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