Mo, Yu, and Li et al. showed that compared to IL-2, the engineered IL-2 partial agonist H9T expanded activated CD8+ T cells, but induced less glycolysis and lower expression of exhaustion and effector molecules, immune checkpoint genes, and pSTAT5, consistent with inducing T cell stemness. HT9 promoted mitochondrial fitness and expression of TCF-1 and CXCR3 proteins. In mouse tumor models, the ability of adoptively transferred H9T-treated CD8+ or CAR T cells to expand, persist, maintain stemness, infiltrate dLN and tumors, control tumors, respond to second tumor challenge, and promote host survival was better than IL-2-treated cells.
Contributed by Paula Hochman
ABSTRACT: Adoptive transfer of antigen-specific T cells represents a major advance in cancer immunotherapy, with robust clinical outcomes in some patients. Both the number of transferred T cells and their differentiation state are critical determinants of effective responses. T cells can be expanded with T cell receptor (TCR)-mediated stimulation and interleukin-2, but this can lead to differentiation into effector T cells and lower therapeutic efficacy, whereas maintenance of a more stem-cell-like state before adoptive transfer is beneficial. Here we show that H9T, an engineered interleukin-2 partial agonist, promotes the expansion of CD8+ T cells without driving terminal differentiation. H9T led to altered STAT5 signalling and mediated distinctive downstream transcriptional, epigenetic and metabolic programs. In addition, H9T treatment sustained the expression of T cell transcription factor 1 (TCF-1) and promoted mitochondrial fitness, thereby facilitating the maintenance of a stem-cell-like state. Moreover, TCR-transgenic and chimeric antigen receptor-modified CD8+ T cells that were expanded with H9T showed robust anti-tumour activity in vivo in mouse models of melanoma and acute lymphoblastic leukaemia. Thus, engineering cytokine variants with distinctive properties is a promising strategy for creating new molecules with translational potential.
Author Info: (1) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (2) Surgery Branch, Na
Author Info: (1) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (2) Surgery Branch, National Cancer Institute, Bethesda, MD, USA. (3) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (4) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (5) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (6) Johns Hopkins University School of Medicine, Baltimore, MD, USA. (7) Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (8) Surgery Branch, National Cancer Institute, Bethesda, MD, USA. (9) National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. (10) National Institute of Diabetes and Digestive and Kidney Diseases, National Institutes of Health, Bethesda, MD, USA. (11) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (12) Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. (13) Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. (14) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (15) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (16) Laboratory of Immunogenetics, National Institute of Allergy and Infectious Diseases, National Institutes of Health, Rockville, MD, USA. (17) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (18) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. (19) Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA. Department of Functional Immune Cell Modulation, Regensburg Center for Interventional Immunology, Regensburg, Germany. University of Regensburg, Regenburg, Germany. (20) Johns Hopkins University School of Medicine, Baltimore, MD, USA. (21) Surgery Branch, National Cancer Institute, Bethesda, MD, USA. drnickrestifo@gmail.com. (22) Department of Molecular and Cellular Physiology and Department of Structural Biology, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu. Howard Hughes Medical Institute, Stanford University School of Medicine, Stanford, CA, USA. kcgarcia@stanford.edu. (23) Laboratory of Molecular Immunology and the Immunology Center, National Heart, Lung and Blood Institute, National Institutes of Health, Bethesda, MD, USA. leonardw@nhlbi.nih.gov.
