Coevolution of Metabolism and Immune Microenvironment as a Driver of Therapeutic Response and Metastasis in ccRCC
Abstract
Scientific Objective/Rationale: Immune checkpoint blockade (ICB) has transformed the lives of patients with the most common form of kidney cancer, clear cell renal cell carcinoma (ccRCC). However, only a fraction of patients respond to ICB, and the majority of those patients go on to develop resistance, creating an urgent need to understand the mechanism of resistance and to develop new therapeutic strategies. ICB therapy works in part by activating metabolic pathways in immune cells in a way that promotes antitumor immunity. Furthermore, experimental studies have shown that the antitumor activity of immune cells can depend sensitively on the availability of specific metabolites in the surrounding environment. These data raise the possibility that the immune response and metabolism of ccRCC tumors coevolve and jointly influence the likelihood that a patient responds to therapy. The Aims of this proposal are to (1) identify metabolites whose abundance is associated with response to therapy, (2) identify the immunometabolic features of those tumor regions which ultimately seed distant metastasis, and (3) determine how ICB treatment affects the metabolism of tumor and immune cells at the level of individual cells. Areas of Emphasis: This project addresses the Cancer Etiology and Therapeutic Response fiscal year 2022 Area of Emphasis for the Kidney Cancer Research Program. The results of this work will have also have significant secondary implications for Biomarkers and Imaging and Novel Therapeutic Strategies. Relevance to Patients: This work will produce a new and fundamental understanding of how tumor and immune cell metabolism influences response to therapy and metastasis. The discoveries produced by this work have several immediate and long-term implications for kidney cancer patients, including for Armed Service Members and their families. By identifying metabolites whose abundance correlates with favorable/unfavorable responses to immunotherapy, it will in the short term chart a path towards precision clinical trials delivering existing and novel metabolically targeted drugs to patients with tumors most likely to respond to treatment. In the long term, these studies will nominate new approaches to non-invasively monitoring therapeutic response with metabolite tracers, which will reduce therapeutic and financial toxicities that kidney cancer patients face during treatment. Innovation: There are three key innovations described in this proposal. First, this work introduces a new integrative paradigm for studying the evolution and therapeutic susceptibility of tumors in terms of both metabolic profiles and immune responses. Second, this work develops an entirely new methodology for imputing (otherwise unavailable) metabolite abundance from widely available RNA sequencing data. Because it is technically difficult to directly measure the abundance of metabolites from tumor tissue, this new method effectively democratizes metabolomics data and raises the possibility of rapidly discovering new metabolite biomarkers as well as new targets for metabolic intervention. Finally, by combining a novel mouse model which faithfully recapitulates the ccRCC immune microenvironment with groundbreaking new technologies for spatial and single cell metabolomic profiling, this work delivers a detailed understanding of the effect of immunotherapy on metabolic phenotypes of the bulk tumor and at single-cell resolution.
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Jan 04, 2024
- Source ID
- HT94252310995
Entities
People
- Eduard Reznik
Organizations
- Sloan-Kettering Institute
- United States Army