Author ORCID Identifier

0000-0003-1446-9574

Date of Graduation

8-2021

Document Type

Thesis (MS)

Program Affiliation

Biomedical Sciences

Degree Name

Masters of Science (MS)

Advisor/Committee Chair

Dr. Amir Jazaeri

Committee Member

Dr. Greg Lizee

Committee Member

Dr. Linghua Wang

Committee Member

Dr. Melinda Yates

Committee Member

Dr. Aung Naing

Abstract

Objective: Half of patients with microsatellite instability high (MSI-H) endometrial cancer are treatment-refractory to pembrolizumab. We sought to evaluate the MSI-H endometrial tumor samples to examine differences in the tumor microenvironment (TME) and identify transcriptomic signatures associated with response/resistance to pembrolizumab. Methods: Archival tumor samples from MSI-H endometrial cancer patients treated at MD Anderson Cancer Center were obtained. Tissue samples originating from patients who did not receive pembrolizumab treatment (“untreated cohort ”; n = 11) were analyzed via RNA sequencing (RNA-seq). Pre-treatment archival tumor samples (“treated cohort”; n = 23) from patients who were later treated with pembrolizumab were collected and analyzed by Exome Capture RNA-seq to identify predictive immuno-genomic signatures associated with treatment response. Multipanel immunofluorescent panel testing was performed on samples in the treated cohort. Results: In the untreated cohort (n=11), the transcriptomic profiles of the samples could be segregated into three subcategories. Four samples were immunologically “hot” as evidenced by an abundance of pro-inflammatory immune cell infiltrate, 3 had a paucity of this infiltrate (“cold”), and 4 samples had intermediate amounts (“warm”). In the treated cohort (n=23), the transcriptomic profiles could similarly be subdivided into three subcatgories. The 14 responders consisted of samples with “hot” (5/5; 100%), “cold” (6/8; 75%), and “warm” TMEs (3/8; 37.5%) while the 7 non-responders consisted of only “cold” (2/8; 25%) and “warm” (5/8; 62.5%) TME samples. Two patients had an unevaluable response to pembrolizumab. We observed an enrichment of fibroblasts and endothelial cell transcriptomic signatures in the samples of the non-responders compared to responders (p = 0.018). Additionally, there was an inverse relationship between enrichment of fibroblast and endothelial cell transcriptomic signatures and strength of treatment response. Responders had higher total (p = 0.029) and PD-L1+ macrophage (p = 0.012) cell densities compared to non-responders.

Conclusions: TME composition appears to be heterogeneous among MSI-H endometrial tumors. Decreased macrophages and increased presence of fibroblasts and endothelial cells in the TME may contribute to innate resistance to pembrolizumab. Adjunctive therapy that optimizes these cellular subpopulations may help overcome pembrolizumab resistance. Future studies are needed to validate these findings

Keywords

endometrial cancer, pembrolizumab, tumor microenvironemnt, microsatellite instability

Available for download on Friday, August 05, 2022

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