Promoting thiol expression increases the durability of antitumor T-cell functions

Area of Science:

• Immunology
• Cell Biology
• Cancer Research

Background:

• Adoptive immunotherapy utilizes ex vivo-expanded CD8(+) T cells, typically with an effector memory phenotype (TEM).
• TEM cells exhibit limited persistence and reduced antitumor efficacy in vivo compared to central memory T cells (TCM cells).
• TCM cells demonstrate better survival in oxidative tumor microenvironments, suggesting superior antioxidative capacity.

Purpose of the Study:

• To investigate the hypothesis that TCM cells possess greater antioxidative capacity than TEM cells.
• To identify molecular differences influencing T cell persistence and antitumor efficacy.
• To explore the role of cell surface thiols as a biomarker for T cell function in immunotherapy.

Main Methods:

• Comparative analysis of cell surface thiol expression and antioxidant molecule levels between TCM and TEM cells.
• Assessment of reactive oxygen and nitrogen species, proliferative capacity, and glycolytic enzyme levels.
• In vivo studies evaluating the persistence and antitumor efficacy of T cells with varying thiol expression levels.

Main Results:

• TCM cells showed increased expression of cell surface thiols and other antioxidant molecules compared to TEM cells.
• Higher antioxidant molecule expression in TCM cells correlated with lower reactive oxygen/nitrogen species, reduced proliferation, and lower glycolytic enzyme levels.
• T cells pretreated with thiol donors demonstrated upregulated thiol levels and antioxidant gene expression.
• CD8(+) T cells with high surface thiol expression exhibited enhanced in vivo persistence and superior tumor control.

Conclusions:

• Elevated levels of reduced cell surface thiols are a key characteristic of T cells capable of controlling tumor growth.
• Surface thiol expression serves as a potential biomarker for predicting T cell efficacy in adoptive immunotherapy.
• Targeting or selecting for thiol-high T cells may improve adoptive T-cell immunotherapy outcomes.