Targeting Inflammatory Signals as Therapeutic Strategies for Peripheral T-Cell Lymphomas
Abstract
Peripheral T-cell lymphomas (PTCLs) comprise a group of aggressive blood cancers that originate from normal T-cells. PTCLs affect middle-aged to older adults and show poor responses to conventional chemotherapy (5? year overall survival rate of about 40%). Therefore, there is an unmet need to develop treatments targeting PTCL- specific changes. One well-known phenomenon is that PTCL cells attract many normal immune cells to their surroundings and form an environment for the lymphoma cells to live and grow; this environment is called the tumor microenvironment. Thus, the tumor microenvironment in PTCLs presents an attractive potential avenue for developing new PTCL-specific treatments. However, how the tumor microenvironment supports PTCLs’ growth is not well understood. Inflammation is a complex cascade of immune reactions involving a network of many cell types. By studying patient samples, we found evidence of increased inflammatory proteins and gene expression in the cancer cells and the tumor microenvironment. Furthermore, while elevated inflammation predicts poor outcomes in PTCL patients, dampening inflammation via a drug called TTI-101 showed an anti- cancer effect in mouse models of PTCL. Thus, the goal of our proposal is to find out if increased inflammation supports the growth of PTCLs and if reducing inflammation in cancer cells and the tumor microenvironment could be a new strategy to treat PTCL. To test our ideas, we will use cutting-edge technologies, including single-cell and spatial transcriptomics, molecular profiling methods that allow scientists to measure all the gene activity in a tissue sample and map where the activity is occurring to understand the composition of cells and inflammation in the tumor microenvironment. We will study tumor samples from patients with PTCL and two mouse models of PTCLs generated in our lab. These mouse models are great tools for our studies, because they carry genetic mutations identical to some PTCL patients and develop tumors mimicking human disease. Moreover, we will study precisely how TTI-101 works to shrink PTCL and determine whether blocking two key inflammatory proteins, IL-6 and TNF-alpha, can reduce PTCL. TT1-101 is a drug now being tested in clinical trials for patients with advanced solid tumors, and there are many available drugs targeting IL-6 and TNF-alpha for the treatment of rheumatic diseases. If these drugs are proven to have a robust anti-cancer effect in our preclinical PTCL mouse models, the findings will be instrumental in developing these drugs into novel treatments for PTCL patients. This work is important and impactful because of the urgent need to improve our knowledge of PTCL and to identify novel targeted therapies for this aggressive disease lacking effective treatment options. Furthermore, our study could improve military readiness by findings new therapeutic agents, which may reduce time in the hospital and minimize PTCL relapse for Service Members, their families, and Veterans. The Principal Investigator of this proposal, Dr. Wen-Hsuan Wendy Lin is an MD-Ph.D. physician-scientists and board-certified hematopathologist at Columbia University Medical Center (CUMC). She has extensive research experience in T-cell lymphoma, immunology, vaccine development, and immunity to viral diseases. Her interdisciplinary background makes her an ideal researcher to lead this project, which requires expertise in the malignant T-cells and immune system that may help to control PTCL. Dr. Lin will work with her career guide, Teresa Palomero Ph.D., a Professor at CUMC and an expert in the mutations that make T-cells cancerous, who has characterized several PTCL mouse models that are valuable to study the disease and evaluate new treatments. Dr. Lin s long-term career goal is to lead an independent research group in translational lymphoma research, focusing on the disease mechanisms and finding cures for peripheral T cell lymphomas. Rec
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310518
Entities
People
- Wen-hsuan Lin
Organizations
- Columbia University
- United States Army