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

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.
Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest.
(Copyright © 2021 Le, Ha, Tran, Newman, Esselen, Dalrymple, Schmelz, Bhandoola, Xue, Singh and Thai.)