Extracellular ATP Functions as a Metabolic Lineage Selection Signal That Stabilizes Tc9 Cells During Adoptive T Cell...

Area of Science:

• Immunology
• Cancer Biology
• Metabolic Signaling

Background:

• Adoptive T cell therapy (ACT) efficacy in solid tumors is hindered by poor T cell persistence in the tumor microenvironment (TME).
• IL-9-producing CD8+ T cells (Tc9) show greater antitumor activity than Tc1 cells, but the reasons for this advantage are unclear.

Purpose of the Study:

• To investigate the role of extracellular ATP (eATP) in shaping T cell responses within the tumor microenvironment during ACT.
• To elucidate the mechanisms by which Tc9 cells achieve superior persistence and efficacy compared to Tc1 cells.

Main Methods:

• Comparative analysis of Tc1 and Tc9 cell responses to extracellular ATP (eATP) in vitro and in vivo.
• Assessment of T cell apoptosis, mitochondrial respiration, and signaling pathways (TGF-β, purinergic signaling) upon ATP exposure.
• Transcriptomic and molecular analyses to identify key molecular differences between Tc1 and Tc9 cells.

Main Results:

• Effective ACT leads to increased intratumoral eATP.
• Tc9 cells exhibit intrinsic resistance to ATP-induced apoptosis, unlike susceptible Tc1 cells.
• ATP exposure enhances Tc9 cell mitochondrial fitness and promotes a tissue-resident memory (TRM) phenotype via TGF-β signaling.
• Purinergic signaling pathways, including P2RX7, are upregulated in Tc9 cells upon ATP stimulation.

Conclusions:

• Extracellular ATP acts as a metabolic selection signal in ACT, favoring the persistence of resilient Tc9 cells.
• Enhanced Tc9 cell persistence is linked to their ability to link purinergic sensing to mitochondrial remodeling and TRM programming.
• These findings provide a basis for improving engineered T cell therapies for solid tumors by manipulating metabolic pathways.