TCR-Independent Metabolic Reprogramming Precedes Lymphoma-Driven Changes in T-cell Fate

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Research

Background:

• Chronic T-cell receptor (TCR) signaling in the tumor microenvironment can lead to T-cell dysfunction.
• Poorly immunogenic tumors might compromise T-cell function by affecting their metabolism.

Purpose of the Study:

• To investigate the temporal metabolic, fate, and functional changes in T cells within B-cell lymphoma models.
• To understand the role of Myc in lymphoma immunogenicity and its impact on T-cell metabolism.

Main Methods:

• Assessed temporal changes in T-cell metabolism, fate, and function in Myc-driven B-cell lymphoma models.
• Utilized metabolomic analyses to identify metabolic reprogramming in CD4+ T cells.
• Examined T-cell mitochondrial function in lymphoma-transplanted transgenic mice.

Main Results:

• Increased lymphoma burden impaired CD4+ T-cell function and promoted regulatory T cell (Treg) and Th1-cell differentiation.
• Early metabolic reprogramming, reduced glucose uptake, and impaired mitochondrial function were observed in CD4+ T cells, preceding fate changes.
• B-cell lymphoma metabolism remained robust, while T-cell mitochondrial functions were impaired in both CD4+ and CD8+ T cells.

Conclusions:

• Early, TCR-independent metabolic interactions with developing lymphomas limit T-cell-mediated immune surveillance.
• Tumor-induced metabolic compromise is a key mechanism of T-cell dysfunction in poorly immunogenic cancers.
• Targeting T-cell metabolism could be a strategy to enhance anti-tumor immunity.