Dissecting Ovarian Cancer Tumor-Immune Microenvironments Through 3D In Situ Molecular Profiling
Abstract
Ovarian cancer treatment failure is a clinically unmet need. High-grade serous ovarian cancer (HGSOC) is a devastating disease. By the time most women are diagnosed, the cancer has often spread throughout their abdomen, and only 15% of patients will survive the 5 year mark. If detected earlier at stages 1 or 2 before metastasis, the 5-year survival rate increases substantially to 80%. It is therefore critically important to understand how the disease develops from its earliest stages. Tumors do not develop in isolation, they interact with healthy cells in the adjacent tissue and together these different cell types form the tumor microenvironment (TME). The TME supports tumor growth and evolves to evade attacks by the immune system and to develop resistance to drug treatment. Making matters more complicated, HGSOC is not a uniform disease with the same features in every woman. Our team has characterized four subtypes of HGSOC: two types are deficient in DNA repair and are defined by mutations in the BRCA 1 and 2 genes, respectively, genes that play a role in correcting DNA damage; two types have an intact DNA repair machinery but show mutations in other genes that affect genome integrity. These classifications are important, as the different tumor types have outcomes: tumors with intact DNA repair are more difficult to treat and women’s prognosis is worse than for tumors with DNA repair deficiencies. Poor understanding of how all cells that comprise ovarian cancers interact represents a key knowledge gap. To be able to target treatment to the individual characteristics of each tumor type, we need to understand how these tumors evolve and how they interact with other cells in their environment. We have recently shown that the subtypes employ unique ways of shaping the TME to avoid recognition by the immune system. For example, we found that BRCA1-mutated tumors recruit a certain type of cytotoxic T cells that normally kill aberrant cells; however, the tumor cells drive T cells on a trajectory that causes them to become dysfunctional. DNA repair intact tumors, on the other hand, recruit only very few immune cells, and the few T cells that are found in proximity to the tumor are classified as naive T cells that have yet to be activated. These differences make it very likely that effective treatment has to be geared towards the particular HGSOC subtype and that a one-size-fits-all approach will not work. Complicating matters even more, tumors vary in the makeup of their microenvironment even within the same patient—the primary tumors in the ovaries often show less infiltration with immune cells than the distant metastatic sites. Study Hypothesis and Experimental Design: In this proposal, we pursue the hypothesis that the different HGSOC subtypes and the different tumor sites within the same patient create unique microenvironments and tumor architectures that drive the avoidance or inactivation of immune surveillance. To test these hypotheses, we will employ the latest spatial profiling techniques to reconstitute the 3D architecture of the tumor microenvironment in the different subtypes and different sites within patients. The teams at Memorial Sloan Kettering Cancer Center will work together with cancer researchers at Cambridge University to use state-of-the-art imaging techniques to identify the millions of individual cells that make up a tumor. An approach called Serial two photon tomography (STPT) first cuts the tumor into very thin slices called sections, then generates images of each section that are computationally reconstructed to produce a 3D image of the tumor. Subsequently the genes and proteins in each section are visualized, which will allow us to see not only the positioning of tumor and immune cells relative to each other, but also their functional activity which in turn will allow us to better understand the mechanism behind drug resistance. In our first Aim, we will compare these 3D
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210759
Entities
People
- Sohrab Shah
Organizations
- Sloan-Kettering Institute
- United States Army