Spreading of cancer cells from primary tumors to healthy organs causes over 90% of cancer deaths. Cancer cells are frequently disseminated from the primary tumor in many patients by the time of diagnosis, so it is urgent to find effective therapeutic targets for disseminated tumor cells. Immunotherapy induces long-lasting and specific immune responses against cancer cells and is a promising treatment approach for metastatic tumors. However, most patients do not benefit from current immunotherapies, indicating that important resistance pathways remain to be discovered. Triple-negative breast cancer (TNBC) is the most metastatic and lethal subtype of human breast cancer. Unfortunately, only a small subset of patients with TNBC respond to immunotherapy. TNBC has a well-known association with epithelial-mesenchymal transition (EMT), where tumor cells transition to a more mesenchymal state that is more metastatic and resistant to immunotherapy. To comprehensively understand how mesenchymal tumor cells evade immune clearance, Dr. Ning has performed a genome-scale functional screen to examine which genes render tumor cells more sensitive or resistant to immune attack. She has identified 432 tumor-intrinsic genes that significantly regulate tumor sensitivity to immune cell killing: Some genes are well-known immune regulators, giving us confidence in the results from this screen. Most discovered genes are novel genes with previously unknown roles in immune regulation, indicating their potential as new immunotherapy targets. Successful validation and characterization of candidate genes will greatly advance our understanding of immune evasion by disseminated tumor cells, which will serve as the molecular basis for developing new immunotherapy approaches for metastatic tumors.
Projects and Grants
Immune evasion by disseminated tumor cells
Dana-Farber Cancer Institute | All Cancers | 2022 | Kai Wucherpfennig, Ph.D.
