Funding tool: Basic research projects
Project-ID: GLF21-1-010
Project start: 01. Dezember 2022
Project end: 30. November 2025
Runtime: 36 months / ongoing
Funding amount: € 299.981,00

Brief summary:
Breast cancer is the most common cancer diagnosed in women and a major challenge in public health. 15-20% of breast tumor patients harbor triple-negative breast cancer (TNBC), a highly aggressive type that does not respond to hormone or monoclonal antibody therapies resulting in high relapse and mortality rates. Screening programs allow the early detection of the primary tumor, improving the patients’ outcome. However, TNBC spreads faster than other breast cancer subtypes. Therefore, there is an urgent need for new approaches for early metastasis detection and novel therapeutics for invasive TNBC. Natural killer (NK) cells are cytotoxic lymphocytes crucial for limiting metastasis but they are often strongly suppressed by the cancer environment. Immune checkpoints are key negative regulators of cytotoxic lymphocytes including NK cells and are important targets for restoring their activity. Checkpoint inhibitor therapies such as anti-PD-(L)1 antibodies have revolutionized the treatment of many cancers but have had limited success against invasive TNBC. It is utmost important to find novel checkpoints and exploit NK cell-based therapies for TNBC. We hypothesize that NK cell-targeting checkpoint inhibitors will prevent metastasis of TNBC. To identify those, we will perform a high-throughput analysis of peripheral NK cells during the progression of metastatic breast cancer. We will use a murine model based on orthotopic injection of breast cancer cells, surgical removal of primary tumor followed by in vivo imaging of metastatic spread. The tools will enable us to track the changes in the transcriptome of peripheral NK cells at defined timepoints using single cell RNA sequencing followed by mass spectrometry proteome analysis. The approach will identify NK subpopulations with exhausted/resting signatures that enrich during the disease progression and their surface molecules that would represent novel therapeutic targets (checkpoints). We will extend our knowledge using peripheral NK cells from TNBC patients. We will analyze their functionality and expression of the newly identified checkpoints. Finally, we will functionally validate the checkpoints in a xenograft model. Our project shall identify an NK-cell checkpoint repertoire relevant for metastasizing TNBC and provide basic knowledge for implementation of peripheral NK-cell screening in TNBC patients. This type of screening would provide a personalized treatment opportunity for metastatic breast cancer patients and could potentially largely prevent metastasis progression. The interdisciplinary project will strengthen the cooperation between basic scientists and clinicians in Krems as well as visibility and competences of the participating institutions.

Keywords:
NK cells, Breast Cancer, Checkpoint inhibitors