Identifying Novel Immune Evasion Tumor Immune Networks as Targets for ccRCC Immunotherapy
Abstract
Each year over 430,000 new cases of kidney cancer are diagnosed globally, and over 179,000 people die from the disease. Once cancer progresses and spreads from the kidney to other vital organs, the disease is largely incurable. Cells from a person s immune system have significant cancer-killing abilities, with therapies harnessing these (called immunotherapies) resulting in remarkable cures for some patients with clear cell kidney cancer (the most common subtype of kidney cancer). However, the vast majority of patients are resistant to these drugs and do not respond. Therefore, there is great interest within the scientific community to develop new immunotherapy treatments for kidney cancer. We have used an exciting new technology known as single-cell genomics to identify novel interactions of immune cells within kidney tumors. We propose that these novel cell interactions may hold the necessary information for developing new immunotherapies. While promising, it is difficult to use this information currently to guide immunotherapy development as this method is too costly to study the large numbers of patients needed to robustly understand the relationship of these cell interactions to kidney cancer progression. Additionally, there are still several technical shortcomings in the technology, most prominently that it does not capture how immune cells interact with one another in three-dimensional (3-D) space. This occurs as tumors must be broken apart during the process of performing single-cell genomics, which loses the spatial orientation of the information of this approach. Indeed, it is well-established that this spatial information is biologically critical for understanding how immune cells work together as communities to defend against cancer. In this project, we will take advantage of another exciting technology known as imaging mass cytometry (IMC) that allows capture of the key information from single-cell genomics but at a fraction of the cost. Importantly, IMC can measure millions of cells across hundreds of patient samples at relatively low cost, allowing us to collect data across tissue samples from a large biobank of clear cell kidney cancer patients at University Health Network (Toronto). In addition, IMC can be applied to patients tumors without the need to break them apart, thereby capturing the molecular information in 3-D space and circumventing the shortcomings of traditional single-cell genomics. Ultimately, using IMC we will be able to identify communities of immune cells that become maladaptive and act to drive kidney cancer progression and spread. These immune cells will then be targeted to develop new immunotherapy treatment strategies. The results of our project will provide the first comprehensive description of how immune cells organize into communities within the kidney cancer tumor microenvironment. Ultimately, we envision our work to fuel new precision medicine-based approaches for kidney cancer by identifying new priority targets for the development of novel immunotherapies and biomarkers. In doing so, our results will lay the groundwork for early phase clinical trials that could deliver novel immunotherapies to patients at risk or who have developed metastatic kidney cancer within 5-10 years.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210870
Entities
People
- Hartland Jackson
Organizations
- Mount Sinai Hospital
- United States Army