Uncovering the Tumor-Immune Microenvironmental Determinants of Immunotherapy Response in Renal Cell Carcinoma Through Ex Vivo Patient-Derived Models
Abstract
Despite tremendous advances in treatment through the development of medications that stimulate the immune system, advanced kidney cancer is still responsible for approximately 15,000 deaths each year in the United States. Kidney cancer is particularly common among Veterans, and so there is a fundamental need to better understand why kidney cancer tumors do or do not respond to current medicines, and to develop new types of treatments to help more patients. A kidney tumor is often composed of hundreds of millions or even billions of individual cells, but not all of those cells are part of the cancer itself. The tumor is actually a diverse ecosystem composed of dozens of different types of cells, including immune cells that may either be trying to attack and eliminate the cancer cells, or conversely, may actually be aiding the growth of the cancer. Altogether, all of the cells and the way they interact with each other is called the microenvironment of the tumor. Prior research from our laboratory and others have studied this tumor microenvironment to try to identify exactly what types of cells are present, how they might interact or talk to each other, and how this might change when kidney cancer grows from a small tumor to a larger one or spreads to other parts of the body. We found that when kidney cancer grows and spreads, the immune cells within the tumor actually become part of the problem. The T cells, which are normally responsible for attacking cancer cells and are the main target of current standardly available immune therapies (called immune checkpoint inhibitors), lose their normal function through a process called exhaustion. However, these T cells do not act alone -- there is another immune cell type in the tumor, the macrophage, that also change in a way that prevents a normal immune response against kidney cancer and promotes the growth of cancer cells. Importantly, these two types of cells appear to be talking to each other (i.e., interacting), with the macrophages instructing the T cells to stop any anti-cancer attack, and the T cells also instructing the macrophages to continue to act in this unproductive fashion. We believe that this crosstalk between these critical immune cell types within the tumor prevents the body s immune system from successfully attacking and controlling kidney cancer. We identified numerous ways that these cell types use to communicate (or interact), and so the next question is clear -- which of these specific interactions can we target with a new drug to restore the normal functioning of the immune system and help it successful eliminate kidney cancer cells? Therefore, our Kidney Cancer Research Program Focus Area is centered on developing novel therapeutic strategies for the treatment of kidney cancer. We believe that the best method for studying this is to use actual kidney cancer tumors from patients to understand these immune cells in a true human context. Our lab has developed and optimized multiple techniques for studying kidney cancer tumor directly from patients -- one system where we isolate just two types of cells and study them in isolation, and another where we actually preserve the full three-dimensional structure of a tumor and all of the dozens of components. These innovative new systems will allow us to ask fundamental questions about kidney cancer: Which interactions can we target with new drugs in order to restore the immune system’s ability to successfully control or eliminate kidney cancer? Once we have identified new targets to bolster the immune system to attack kidney cancer, we next ask which patients are most likely to benefit from a new therapy? To do this, we re-analyze a large set of data that we previously published to ask which of these new targets or interactions are more commonly found in tumors that are resistant to current kidney cancer therapies, as we believe patients with these therapy-resistant tumors would be most lik
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310735
Entities
People
- David A Braun
Organizations
- United States Army
- Yale University