Exploring Antitumor Immune Response in a Novel MLL3-Mutant Breast Cancer Model
Abstract
The research proposed here will directly address two overarching challenges facing breast cancer treatment: (i) identify what drives breast cancer growth; determine how to stop it and (ii) revolutionize treatment regimens by replacing them with ones that are more effective and less toxic. Immunotherapies held great potential for cancer treatments that have long-lasting effects on eliminating cancer growth and dramatically improve patient survival. However, the success of such revolutionary therapies in breast cancers is still limited. This points to the existence of unknown mechanisms by which breast cancers can suppress tumor immunity. Gaining insights to these mechanisms is critical for successfully developing immunotherapies for breast cancer. To study these mechanisms, we need experimental systems that can closely mimic the tumor evolution process in human patients. To this end, we have developed and are making use of a novel approach that allows us to rapidly generate mouse tumor models that are driven by the exact same human cancer gene mutations and to study how these mutations alter and suppress the immune system, and test potential therapeutic approaches. Using this novel platform, we have discovered that frequently occurring mutations in a gene called MLL3, associated to other mutations of poor prognosis in human patients, have the ability to promote tumor growth and potently suppress effective immune responses within the breast tumors. Our study is investigating and elucidating the underpinning mechanisms by which MLL3 mutations, associated with other poor-prognosis mutations, promote tumor development and cause immune suppression in tumors. Using this novel preclinical model, we have recently discovered (i) how MLL3 mutation accelerates tumor onset and (ii) an essential role for tumor infiltrating B cells, a subset of immune white blood cells, in accelerating tumor growth. B cells often represent a substantial proportion of white blood cells in human tumors, yet their roles only begin to be explored. Harnessing these mechanistic findings, our long-term goals are to develop novel immunotherapeutic strategies for MLL3 mutant cancers by restoring the anti-tumor function of immune cells, possibly through selective targeting of these tumor infiltrating B cells. MLL3 gene alterations occur in 8%-27% of human breast cancers and these patients have particularly poor clinical outcome. Thus, successful outcomes of our study will have a major impact on improving breast cancer patient survival.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110207
Entities
People
- Wenjun Guo
Organizations
- Albert Einstein College of Medicine
- United States Army