The Role of TREM2-Expressing Macrophages in the Obesity Paradox in Clear Cell Renal Cell Carcinoma
Abstract
While people who are obese are more likely to develop kidney cancer, they paradoxically have better prognoses and are more likely to benefit from therapies that use the power of the immune system -- known as immunotherapies -- to attack tumors. In this project, we will investigate differences in the immune response to kidney cancer between obese and normal-weight individuals using both patient samples and mouse models. Our preliminary investigations suggest that these differences are likely mediated by interactions between the fat adjacent to kidney tumors and the tumors themselves, as the immune properties of that fat differ between obese and normal-weight individuals. These interactions include expansion of immune cells called macrophages, which are known to have both pro- and anti-tumor effects. Specifically, we have found macrophages expressing a fat molecule receptor called TREM2 to be present at high numbers in tumor-adjacent fat and lower numbers in tumors. Intratumoral TREM2 macrophages have been shown to support tumor growth. Thus, our planned studies test the hypothesis that differences in the distribution of TREM2 macrophages between tumors and tumor-adjacent fat are important to control tumor growth, in addition to broadly characterizing how the immune response to kidney tumors is affected by obesity in tumors and adjacent fat. This proposal addresses the following Kidney Cancer Research Program Areas of Emphasis: microenvironment and immunology, new disease model systems, and mechanisms of response and resistance, and has potential to lead to biomarker and therapeutic development. In the short term, our proposal will help clarify the reasons why obese patients with kidney cancer have less aggressive tumors, and whether this is controlled by immune cells. These studies will also yield important knowledge that may help predict which patients, regardless of weight, have tumors that will likely be controlled by immunotherapies, and may also suggest new ways to improve their efficacy through combination with other treatments. These candidate biomarkers and therapeutic targets would require further investigation to confirm their utility and relevance, followed by clinical trials in the next 3 to 5 years. The major innovation of this research lies in its focus on the role of the immune response in the obesity paradox, and immune interactions between fat and kidney tumors, which are just beginning to be studied. In addition, the project employs a new mouse model in which kidney tumors can be induced using gene-editing technology, allowing examination of immune responses that would not be possible in other models, and uses cutting-edge sequencing methods to characterize how gene expression patterns vary across spatial dimensions in adjacent tissues. Finally, we will utilize state-of-the-art techniques to eliminate TREM2 macrophages from these mice to determine their specific role in kidney cancer development and immunotherapy response. Given the novelty of our research question and the wide-ranging nature of our planned experiments, this project will have a major impact on the field of kidney cancer research by opening up many new lines of study. These novel areas of research may then also lead to new approaches to outcome prediction and treatment.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110941
Entities
People
- Abraham Hakimi
Organizations
- Sloan-Kettering Institute
- United States Army