Journal Article

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

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

2021

Overview

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.

• Publisher: Frontiers Media SA,Frontiers Media S.A
• Subject: Animals / Antibodies / Ascites / Cbx3/HP1γ / CD4 antigen / CD8 antigen / CD8+ T-cell persistence / CD8-Positive T-Lymphocytes - immunology / CD8-Positive T-Lymphocytes - metabolism / CD8-Positive T-Lymphocytes - transplantation / Cell Differentiation / Cell Line, Tumor / Chemokines / Chromatin remodeling / Chromobox Protein Homolog 5 - genetics / Chromobox Protein Homolog 5 - metabolism / Chromosomal Proteins, Non-Histone - genetics / Chromosomal Proteins, Non-Histone - metabolism / Cloning / Coculture Techniques / Effector cells / Female / Flow cytometry / Gene Expression Regulation, Neoplastic / Hepatocyte nuclear factor 1 / IL-21 receptor / Immune checkpoint inhibitors / Immunology / Immunotherapy, Adoptive / Interleukin-21 Receptor alpha Subunit - genetics / Interleukin-21 Receptor alpha Subunit - metabolism / LEF protein / LEF-1 / Lymphocyte Activation / Lymphocytes / Lymphocytes T / 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 / Neuroblastoma - genetics / Neuroblastoma - immunology / Neuroblastoma - metabolism / Neuroblastoma - therapy / Ovarian cancer / Ovarian Neoplasms - genetics / Ovarian Neoplasms - immunology / Ovarian Neoplasms - metabolism / Ovarian Neoplasms - therapy / Ovaries / Progenitor cells / Proteins / RNA polymerase / Senescence / Signal Transduction / Solid tumors / T-Lymphocytes, Regulatory - immunology / T-Lymphocytes, Regulatory - metabolism / Transcription initiation / Tumor Burden / Tumor Microenvironment / Tumors / Viral infections