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=12

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=<p>Immune checkpoint blockade (ICB) relieves CD8<sup>+</sup> 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<sup>+</sup> T-cell persistence for ICB non-responsive and resistant tumors remains elusive. We demonstrate that targeting <italic>Cbx3</italic>/HP1γ in CD8<sup>+</sup> T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity at <italic>Lef1</italic> and <italic>Il21r</italic>. LEF-1 and IL-21R are necessary for <italic>Cbx3</italic>/HP1γ-deficient CD8<sup>+</sup> effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence of <italic>Cbx3</italic>/HP1γ-deficient CD8<sup>+</sup> T cells facilitates remodeling of the tumor chemokine/receptor landscape ensuring their optimal invasion at the expense of CD4<sup>+</sup> Tregs. Thus, CD8<sup>+</sup> T cells heightened effector function consequent to <italic>Cbx3</italic>/HP1γ deficiency may be distinct from functional reactivation by ICB, implicating <italic>Cbx3</italic>/HP1γ as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumors.</p>