AUTHOR=Le Phuong T. , Ha Ngoc , Tran Ngan K. , Newman Andrew G. , Esselen Katharine M. , Dalrymple John L. , Schmelz Eva M. , Bhandoola Avinash , Xue Hai-Hui , Singh Prim B. , Thai To-Ha 

TITLE=Targeting Cbx3/HP1γ Induces LEF-1 and IL-21R to Promote Tumor-Infiltrating CD8 T-Cell Persistence

JOURNAL=Frontiers in Immunology

VOLUME=Volume 12 - 2021

YEAR=2021

URL=https://www.frontiersin.org/journals/immunology/articles/10.3389/fimmu.2021.738958

DOI=10.3389/fimmu.2021.738958

ISSN=1664-3224

ABSTRACT=Immune checkpoint blockade (ICB) can relieve CD8+ T-cell exhaustion in most mutated tumors,
and TCF-1 plays an essential role. 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/HP1g in CD8+ T cells causes augmented
transcription initiation and chromatin remodeling at Lef1 and Il21r leading to their increased
transcriptional activity. LEF-1 and IL-21R are required for Cbx3/HP1g-deficient CD8+ effector T
cells to persist and control ovarian cancer, melanoma and neuroblastoma in preclinical models.
The enhanced persistence of Cbx3/HP1g-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/HP1g deficiency may be distinct
from functional reactivation by ICB, implicating Cbx3/HP1g as a viable cancer T-cell-based
therapy target for ICB resistant, non-responsive solid tumors.