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

• Published in: Frontiers in immunology 2021-10, Vol.12, p.738958-738958
• Main Authors: 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
• Format: Article
• Language: English
• Subjects: Animals; Cbx3/HP1γ; CD8+ T-cell persistence; CD8-Positive T-Lymphocytes - immunology; CD8-Positive T-Lymphocytes - metabolism; CD8-Positive T-Lymphocytes - transplantation; Cell Differentiation; Cell Line, Tumor; Chromobox Protein Homolog 5 - genetics; Chromobox Protein Homolog 5 - metabolism; Chromosomal Proteins, Non-Histone - genetics; Chromosomal Proteins, Non-Histone - metabolism; Coculture Techniques; Female; Gene Expression Regulation, Neoplastic; IL-21 receptor; Immunology; Immunotherapy, Adoptive; Interleukin-21 Receptor alpha Subunit - genetics; Interleukin-21 Receptor alpha Subunit - metabolism; LEF-1; Lymphocyte Activation; Lymphocytes, Tumor-Infiltrating - immunology; Lymphocytes, Tumor-Infiltrating - metabolism; Lymphoid Enhancer-Binding Factor 1 - genetics; Lymphoid Enhancer-Binding Factor 1 - metabolism; melanoma; Melanoma, Experimental - genetics; Melanoma, Experimental - immunology; Melanoma, Experimental - metabolism; Melanoma, Experimental - therapy; Mice; Mice, Inbred C57BL; Mice, Knockout; Mice, Transgenic; Neuroblastoma - genetics; Neuroblastoma - immunology; Neuroblastoma - metabolism; Neuroblastoma - therapy; ovarian cancer; Ovarian Neoplasms - genetics; Ovarian Neoplasms - immunology; Ovarian Neoplasms - metabolism; Ovarian Neoplasms - therapy; Signal Transduction; T-Lymphocytes, Regulatory - immunology; T-Lymphocytes, Regulatory - metabolism; Tumor Burden; Tumor Microenvironment
• ISSN: 1664-3224; 1664-3224
• DOI: 10.3389/fimmu.2021.738958

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