Integrative Analysis of Tumor Immune Microenvironment in Gynecologic Cancer: Dissecting the Interaction among Tumor Immune Composition, Genomic Aberrations, and Clinicopathological Features in Ovarian and Endometrial Carcinomas.

This study aims to categorize the tumor immune microenvironment (TIME) in major types of gynecologic cancer. TIME can be described according to the abundance, type, localization, and structures of tumor immune infiltrates. TIME is heterogeneous among different cancer types, and even among tumors of the same type in different individuals. It is probably shaped by both host factors and genetic makeup of individual tumors. We plan to explore the relationship between TIME and clinicopathological features, molecular subgroups, and genomic aberrations, in hopes of answering the following questions: (1) How is TIME different among different histologic types, tumor grades, tumor stages, and molecular subtypes of gynecologic cancer? (2) How does TIME predict clinical outcome and treatment response differently in different types of gynecologic cancer? (3) What are the genomic aberrations that shape the TIME in different types of gynecologic cancers? [Specific Aim 1]: To evaluate the TIME in major types of gynecologic cancer. Specifically, we plan to assess the tumor-infiltrating immune composition, including T cells, CD8+ T cells, Treg cells, Tfh cells, B cells, M1 and M2 macrophages, neutrophils, and eosinophils, in surgically resected ovarian and endometrial carcinomas by immunohistochemistry and whole slide imaging analysis. We will investigate the relationship among different types of immune infiltrate in different histologic types of gynecologic cancers, and try to identify the types or ratios of tumor-infiltrating immune cells that have significant impact on clinical outcome for each type of gynecologic cancer studied. [Specific Aim 2]: To investigate the interplay between molecular subtypes of endometrial carcinoma and TIME. Specifically, we will identify the TIME associated with certain molecular subtype of endometrial carcinoma. We will also identify the types or ratios of tumor-infiltrating immune cells that can predict clinical outcome for certain molecular subtypes of endometrial carcinoma. [Specific Aim 3]: To investigate whether and how genome-wide copy number aberrations shape TIME in ovarian cancers. Specifically, we plan to explore the relationship between TIME and chromosomal instability, as well as genomic scar signatures associated with homologous recombination deficiency. In addition, we will try to identify amplifications/deletions of cancer-associated and immune-related genes that are associated with certain tumor immune profiles in ovarian high-grade serous carcinoma and clear cell carcinoma. This work will likely generate clinically significant results, as better understanding of TIME in the context of tumor histotypes and molecular subtypes holds great potential for discovery of better biomarkers for selection of patients with gynecologic cancer for immune checkpoint blockade-based therapies. Moreover, we expect to identify novel association between genomic aberrations and certain tumor immune contexture. This will not only provide insights into future mechanistic research but also offer clues to synergistic combination of targeted therapy and immunotherapy.

Project ID:PC10901-1393
External Project ID:MOST108-2320-B182-036-MY3