Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence
Le P.T. Ha N. Tran N.K. Newman A.G. Esselen K.M. Dalrymple J.L. Schmelz E.M. Bhandoola A. Xue H.-H. Singh P.B. Thai T.-H.
6 October 2021Frontiers Media S.A.
Frontiers in Immunology
2021#12
Immune checkpoint blockade (ICB) relieves CD8+ T-cell exhaustion in most mutated tumors, and TCF-1 is implicated in converting progenitor exhausted cells to functional effector cells. However, identifying mechanisms that can prevent functional senescence and potentiate CD8+ T-cell persistence for ICB non-responsive and resistant tumors remains elusive. We demonstrate that targeting Cbx3/HP1γ in CD8+ T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity at Lef1 and Il21r. LEF-1 and IL-21R are necessary for Cbx3/HP1γ-deficient CD8+ effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence of Cbx3/HP1γ-deficient CD8+ T cells facilitates remodeling of the tumor chemokine/receptor landscape ensuring their optimal invasion at the expense of CD4+ Tregs. Thus, CD8+ T cells heightened effector function consequent to Cbx3/HP1γ deficiency may be distinct from functional reactivation by ICB, implicating Cbx3/HP1γ as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumors. © Copyright
Cbx3/HP1γ , CD8+ T-cell persistence , IL-21 receptor , LEF-1 , melanoma , ovarian cancer
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Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
Institute of Cell and Neurobiology, Charité-Universitätsmedizin Berlin, Corporate Member of Freie Universität Berlin, Humboldt-Universität zu Berlin, Berlin Institute of Health, Berlin, Germany
Division of Gynecologic Oncology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
Department of Human Nutrition, Food, and Exercise, Virginia Tech, Blacksburg, VA, United States
Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
Center for Discovery and Innovation, Hackensack University Medical Center, Nutley, NJ, United States
Nazarbayev University School of Medicine, Nur-Sultan, Kazakhstan
Cancer Research Institute, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, United States
Department of Physiology, Anatomy and Genetics, Oxford University, Oxford, Oxfordshire, United Kingdom
Center for Drug Discovery, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, United States
Department of Pathology
Institute of Cell and Neurobiology
Division of Gynecologic Oncology
Department of Human Nutrition
Center for Cancer Research
Center for Discovery and Innovation
Nazarbayev University School of Medicine
Cancer Research Institute
Department of Physiology
Center for Drug Discovery
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