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 targetingCbx3/HP1γ in CD8⁺T cells augments transcription initiation and chromatin remodeling leading to increased transcriptional activity atLef1andIl21r. LEF-1 and IL-21R are necessary forCbx3/HP1γ-deficient CD8⁺effector T cells to persist and control ovarian cancer, melanoma, and neuroblastoma in preclinical models. The enhanced persistence ofCbx3/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 toCbx3/HP1γ deficiency may be distinct from functional reactivation by ICB, implicatingCbx3/HP1γ as a viable cancer T-cell-based therapy target for ICB resistant, non-responsive solid tumors.