Metabolic Competition in the Tumor Microenvironment Is a Driver of Cancer Progression
Chih-Hao Chang1, Jing Qiu1, David O'Sullivan1
1Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, MO, 63110, USA.
Abstract:
Failure of T cells to protect against cancer is thought to result from lack of antigen recognition, chronic activation, and/or suppression by other cells. Using a mouse sarcoma model, we show that glucose consumption by tumors metabolically restricts T cells, leading to their dampened mTOR activity, glycolytic capacity, and IFN-γ production, thereby allowing tumor progression. We show that enhancing glycolysis in an antigenic "regressor" tumor is sufficient to override the protective ability of T cells to control tumor growth. We also show that checkpoint blockade antibodies against CTLA-4, PD-1, and PD-L1, which are used clinically, restore glucose in tumor microenvironment, permitting T cell glycolysis and IFN-γ production. Furthermore, we found that blocking PD-L1 directly on tumors dampens glycolysis by inhibiting mTOR activity and decreasing expression of glycolysis enzymes, reflecting a role for PD-L1 in tumor glucose utilization. Our results establish that tumor-imposed metabolic restrictions can mediate T cell hyporesponsiveness during cancer.
Insights
Tumors restrict T cells by consuming glucose, impairing their anti-cancer functions. Restoring glucose metabolism in T cells via immunotherapy can enhance their cancer-fighting ability.
Area of Science:
- Immunology
- Cancer Biology
- Metabolic Pathways
Background:
- T cell-mediated cancer immunity is often hindered by factors like antigen recognition, chronic activation, or immune suppression.
- Tumor microenvironments present unique challenges to immune cell function.
Purpose of the Study:
- To investigate the role of tumor glucose consumption in restricting T cell anti-cancer activity.
- To explore how metabolic interventions and immunotherapies impact T cell function within the tumor microenvironment.
Main Methods:
- Utilized a mouse sarcoma model to study T cell responses.
- Analyzed T cell metabolic activity, including mTOR signaling, glycolysis, and Interferon-gamma (IFN-γ) production.
- Investigated the effects of enhancing tumor glycolysis and administering checkpoint blockade antibodies (anti-CTLA-4, anti-PD-1, anti-PD-L1).
- Examined the direct impact of PD-L1 blockade on tumor glycolysis and T cell function.
Main Results:
- Tumor glucose consumption metabolically restricts T cells, reducing their mTOR activity, glycolytic capacity, and IFN-γ production, which promotes tumor growth.
- Enhancing glycolysis in tumors can overcome T cell-mediated tumor control.
- Clinical checkpoint blockade antibodies restore tumor microenvironment glucose, enabling T cell glycolysis and IFN-γ production.
- Blocking PD-L1 on tumors inhibits their glycolysis by affecting mTOR activity and key glycolytic enzymes.
Conclusions:
- Tumor-imposed metabolic restrictions are a key mechanism mediating T cell hyporesponsiveness in cancer.
- Targeting tumor metabolism and leveraging immunotherapy can restore T cell function for improved cancer immunity.
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