Tumor-Intrinsic and Tumor-Extrinsic Determinants of Immune Responsiveness in MiT/TFE Translocation Renal Cell Carcinoma
Abstract
Objective and Rationale: Kidney cancer is one of the five most common cancers diagnosed amongst United States Veterans and accounts for over 79,000 new cases and 14,000 deaths each year in the United States. There are many different types of kidney cancer. About 70% of kidney cancers are of clear cell kidney cancer variety. The other 30% of kidney cancers are called non-clear cell kidney cancer, of which there are multiple subtypes. One specific subtype of non-clear cell kidney (renal) cancer is called translocation renal cell carcinoma. This subtype accounts for 1%-5% of all kidney cancers in adults and over 40% of kidney cancers in children. Translocation kidney cancer is rare, aggressive, and usually occurs in younger, female patients. Translocation kidney cancer is so named because on the molecular level, it has a joining (translocation) between two genes. One of the genes in the translocation is a transcription factor (protein that binds DNA) in a family of genes named MiT/TFE. The second gene in the translocation can be any one of several possible partner genes. The protein created by the joining of the MiT/TFE gene and the partner gene is known as an MiT/TFE fusion. Previous studies, including our prior work, support the notion that the MiT/TFE fusion is the key mutation in translocation renal cell carcinoma, and hence the primary therapeutic target in this disease. Over the past several years, there have been many promising treatments tested and approved for clear cell kidney cancer, including various types of immunotherapies, which use our body s own immune system to attack and destroy cancer. However, these therapies approved for clear cell kidney cancer are not effective in patients with translocation renal cell carcinoma. This is because clear cell kidney cancer and translocation kidney cancer have significant molecular and immunological differences, which alter how the immune system recognizes these cancers. As a result, treatments developed for clear cell kidney cancer cannot be readily used to treat patients with translocation kidney cancer. Because translocation kidney cancer is rare and recently described, it has not been extensively studied. Therefore, there are currently no therapies designed specifically for this subtype of kidney cancer, which remains a major unmet need in the field. This proposal seeks to answer several fundamental questions about translocation kidney cancer, with the goal of developing immunotherapies tailored to this subtype. First, how exactly does translocation kidney cancer differ from clear cell kidney cancer, and what are the immune cells involved in detecting these two subtypes of kidney cancer? Second, how are the immune cells detecting translocation kidney cancer? Here, we will specifically test the hypothesis that immune cells recognize translocation kidney cancer through MiT/TFE fusions, which can then be targeted for cancer immunotherapies. Third, what are the specific characteristics of the immune cells that recognize MiT/TFE fusions in translocation kidney cancer? Answering these questions will enhance our understanding of translocation renal cell carcinoma and help in the development of new therapies for this disease. Clinical applicability/Impact: This research is designed to improve the lives of patients with translocation renal cell carcinoma, a rare and aggressive subtype of kidney cancer, that has major molecular and immunological differences from clear cell kidney cancer. The studies proposed here are necessary to gain a complete picture of the immune cells and immune responses involved in translocation kidney cancer, important to fully understand this subtype. Our hope is that this proposal will identify new targets for translocation kidney cancer within the next 3 years. Longer term (~5-8 years), this will allow us to develop personalized immunotherapies and combination therapies that are specifically tailored to tran
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310066
Entities
People
- Prathyusha Konda
Organizations
- Dana–Farber Cancer Institute
- United States Army