While checkpoint inhibitors and chimeric antigen receptor (CAR) T cells undergo widespread investigation as approaches to unleash the immune system?s tumor-targeting abilities, the mechanisms by which these therapies fail is the subject of great debate. In the setting of solid tumors, it is believed that the microenvironment is hostile, excluding T cells and/or inhibiting their ability to proliferate or be activated. A dearth of metabolic precursors, most notably glucose, has been implicated as inhibiting T-cell function. There remains an unmet need for approaches to better understand T-cell metabolism and its impact on tumors in vivo, as well as a method to modulate this metabolic limitation to overcome T-cell exhaustion. Given extensive preliminary data, we have developed a model system to explore T-cell exhaustion using primary T cells stimulated in vitro. We have also identified a metabolic mechanism that can overcome limited glycolytic flux by utilizing another biologically available substrate: fructose. Moreover, we have optimized methods to trace metabolism in vitro and in vivo using hyperpolarized magnetic resonance (HP MR), which can detect changes in metabolism in real time. Taken together, these approaches provide a platform for studying immunometabolism both in vitro and in vivo in a syngeneic model of melanoma, which has great potential for future immunotherapeutics. The objective of this innovative proposal is to utilize our in vitro and in vivo models to interrogate the metabolism of T cells.
In Aim 1, we will explore T-cell metabolism in vivo in order to reverse the reduced glycolytic flux in exhausted T cells.
In Aim 2, taking advantage of our newly developed HP fructose, we will metabolically image fructose metabolism in T cells using our newly developed HP microNMR and in vivo with HP magnetic resonance spectroscopic imaging (MRSI). We will then translate this approach to tumor-bearing mice in Aim 3, where we combine T-cell therapy and HP MRI to treat a syngeneic model of melanoma. It is the overarching goal of this proposal to use these novel approaches in metabolism and metabolic imaging to further our understanding of immunometabolism and lay the foundation for future immunotherapy strategies in patients.

Public Health Relevance

The overarching goal of the proposed research is to explore the metabolism of T cells in order to develop metabolic imaging approaches with hyperpolarized (HP) MR. It has been shown that T-cell therapies are hindered by a dearth of metabolic precursors in the tumor microenvironment. In this work, we aim to better understand T-cell metabolism using novel tools and models and to develop strategies to overcome metabolic limitations. We aim to enhance the glycolytic metabolism of T cells by giving them a unique endogenous substrate for their metabolism, fructose, which is present in our diet but not normally metabolized by a wide range of cancers. This work will advance the treatment of a range of solid tumors and develop non-invasive metabolic biomarkers for cancer immunotherapy.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA248364-01A1
Application #
10121638
Study Section
Imaging Probes and Contrast Agents Study Section (IPCA)
Program Officer
Mccarthy, Susan A
Project Start
2020-12-11
Project End
2025-11-30
Budget Start
2020-12-11
Budget End
2021-11-30
Support Year
1
Fiscal Year
2021
Total Cost
Indirect Cost
Name
Sloan-Kettering Institute for Cancer Research
Department
Type
DUNS #
064931884
City
New York
State
NY
Country
United States
Zip Code
10065