Haften and Sluis et al. showed that transient cell cycle arrest activated CD8⁺ T cells into a metabolically primed, IL-2-producing effector state that supported rapid proliferation and enhanced antitumor activity after release. During arrest, CD8+ T cells upregulated glycolysis, cholesterol metabolism, and mitochondrial activity, acquiring a memory-like metabolic and transcriptional state. Post-arrest proliferation was partially mTORC1-independent and relied on elevated, IL-2-mediated STAT5 signaling. Transient cell cycle arrest enhanced CD8+ T cell-mediated tumor control in immune checkpoint blockade, adoptive cell transfer, and vaccination models.
Contributed by Shishir Pant
ABSTRACT: Cell cycle-inhibiting chemotherapeutics are widely used in cancer treatment. Although the primary aim is to block tumor cell proliferation, their clinical efficacy also involves specific effector CD8(+) T cells that undergo synchronized proliferation and differentiation. How CD8(+) T cells are programmed when these processes are uncoupled, as occurs during cell cycle inhibition, is unclear. Here, we show that activated CD8(+) T cells arrested in their cell cycle can still undergo effector differentiation. Cell cycle-arrested CD8(+) T cells become metabolically reprogrammed into a highly energized state, enabling rapid and enhanced proliferation upon release from arrest. This metabolic imprinting is driven by increased nutrient uptake, storage and processing, leading to enhanced glycolysis in cell cycle-arrested cells. The nutrient sensible mTORC1 pathway, however, was not crucial. Instead, elevated interleukin-2 production during arrest activates STAT5 signaling, which supports expansion of the energized CD8(+) T cells following arrest. Transient arrest in vivo enables superior CD8(+) T cell-mediated tumor control across models of immune checkpoint blockade, adoptive cell transfer and therapeutic vaccination. Thus, transient uncoupling of CD8(+) T cell differentiation from cell cycle progression programs a favorable metabolic state that supports the efficacy of effector T cell-mediated immunotherapies.
Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. De
Author Info: (1) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (2) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (3) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (4) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (5) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (6) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (7) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (8) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (9) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (10) Center for Proteomics and Metabolomics, Leiden University Medical Center, Leiden, the Netherlands. (11) Center for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands. (12) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (13) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (14) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (15) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (16) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (17) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. (18) Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (19) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (20) Department of Medical Oncology, Leiden University Medical Center, Leiden, the Netherlands. (21) Department of Pathology, Leiden University Medical Center, Leiden, the Netherlands. (22) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (23) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (24) Department of Biomedical Data Sciences, Sequencing Analysis Support Core, Leiden University Medical Center, Leiden, the Netherlands. (25) Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, the Netherlands. (26) Center for Infectious Diseases, Leiden University Medical Center, Leiden, the Netherlands. (27) Department of Medical Oncology, Oncode Institute, Leiden University Medical Center, Leiden, the Netherlands. (28) Department of Immunology, Leiden University Medical Center, Leiden, the Netherlands. r.arens@lumc.nl.
