Professor of Immunology Mayo Clin. Col. of Med. and Sci. Rochester, Minnesota, United States
Introduction/Rationale: We recently identified a population of resilient CD8⁺ T cells, which uphold their cytotoxic capacity to eliminate tumor cells, in patients with advanced solid tumors in responses to ICI therapy. Among these resilient CD8⁺ T cells, we observed upregulation of ME1 and downregulation of DUSP2 in responders to ICI or ICI-based combination therapy. However, the mechanistic role of altered ME1 and DUSP2 expression in shaping resilient CD8⁺ T cell responses in cancer remains to be fully elucidated.
Methods: We employed single cell RNA-sequencing, bulk RNA-sequencing, and ATAC-sequencing analyses to investigate how induced altered expression of DUSP2 and ME1 regulates transcription of genes encoding effector molecules in both human and mouse CD8⁺ T cells. These findings were further validated through functional assays assessing T cell effector activity. Additionally, we utilized CD8⁺ T cell-specific DUSP2 knockout (KO) and ME1 overexpressing mouse models to define the roles of these genes in effector T cell differentiation and antitumor responses in vivo.
Results: DUSP2 downregulation enhances both the expression of cytotoxic effector molecules and cytotoxic activity in CD8⁺ T cells. Mechanistically, reduced DUSP2 expression promoted chromatin accessibility at effector gene loci by balancing the nuclear residency of BAF and NuRD, two chromatin remodeling complexes with opposing functions. In parallel, induced ME1 overexpression enabled CD8⁺ T cells to bypass the classical glycolysis pathway in favor of the pentose phosphate pathway, thereby boosting ATP production while minimizing excessive ROS accumulation. This metabolic shift also contributed to increased effector molecule expression, potentially via an epigenetic mechanism.
Conclusion: Our study reveals a functional adaptive mechanism by which resilient CD8⁺ T cells maintain their effector function through integrated reprogramming of epigenetic regulation and metabolic fitness, enabling compensation for metabolic stress in the TME.
