Metabolic Demands and Determinants in the RCC Tumor Microenvironment
Abstract
Key observations in the clinic and studies in the laboratory are converging on a renewed need to examine an immune cell type known as macrophages in the context of kidney tumors. First, our group has been pursuing the conundrum that clear cell renal cell carcinoma (ccRCC) is known to harbor potent metabolic regulatory gene mutations that should drive glucose uptake, yet the tumor is often hard to detect on radioactive glucose (FDG) PET scans. We recently showed that in human ccRCC the glucose in the tumor was available in sufficient quantities for all the cells present, but that, surprisingly, it was immune cells rather than cancer cells that consumed the bulk of available glucose across a variety of mouse tumor models. In fact, it was a subset of immune cells called macrophages that were the dominant consumers of glucose. We also showed that while the metabolic preferences of individual cells in the tumor were hard-wired, they may be modified by applying different metabolic inhibitor drugs. Macrophages move into tissues and are generally considered to be waste consumers and are well-known for their role in clearing debris. These cells are plentiful in tumors, where they clean up such litter as dead cancer cells. They also play another important role to present cancer antigens to the immune system. Here, portions of the digested cancer cell are displayed on the surface of the macrophage to train the immune system to recognize the cancer cells as foreign. This activity is important to prime the tumor T cells to spring into action when they receive the signal from immunotherapy checkpoint inhibitors. However, we also know that macrophages come in many different flavors: Some macrophages function to stimulate immune response, and others dampen immune response, among a myriad of other activities and functions. Our group recently observed that a subset of macrophages that are defined by sophisticated single-cell gene expression are closely tied to outcome, with the presence of these cells indicating more risk for metastasis. We now propose to bring these lines of investigation together in a translational research partnership that will, for the first time (1) examine the cancer cell genetic features that influence macrophage infiltration in the tumor, (2) functionally characterize the full complement of macrophage cells present in tumors, and (3) establish spatial relationships between macrophage subsets and other cells in the tumor microenvironment. The goal in these studies is to move our observations squarely into the human tumor space, and to create a survey of cells using fresh human tumor specimens for the purpose of developing biomarkers, planning future radiolabeled imaging strategies for tumor detection, and developing treatments that take advantage of the macrophage component of tumors. This project will help patients with ccRCC directly, by helping us understand what information is being provided in PET scans, as well as by revealing interactions between tumor cell types that influence metabolic activity. The immediate potential clinical application is to use FDG-PET scans in a biomarker strategy, and to develop macrophage-targeted treatments that facilitate T cell response to immunotherapy, both of which are approaches that could be supported for development before the end of this grant period.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 28, 2022
- Source ID
- W81XWH2210418
Entities
People
- Wendy Rathmell
Organizations
- United States Army
- Vanderbilt University