BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy.

Autor:	Salmon AJ; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Shavkunov AS; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Miao Q; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Jarjour NN; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Keshari S; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Esaulova E; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Williams CD; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Ward JP; Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri., Highsmith AM; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Pineda JE; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Taneja R; Department of Physiology, Healthy Longevity Translation Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore., Chen K; Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas., Edelson BT; Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri., Gubin MM; Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.; The Parker Institute for Cancer Immunotherapy, The University of Texas MD Anderson Cancer Center, Houston, Texas.
Jazyk:	angličtina
Zdroj:	Cancer immunology research [Cancer Immunol Res] 2022 May 03; Vol. 10 (5), pp. 597-611.
DOI:	10.1158/2326-6066.CIR-21-0129
Abstrakt:	Immune checkpoint therapy (ICT) using antibody blockade of programmed cell death protein 1 (PD-1) or cytotoxic T-lymphocyte-associated protein 4 (CTLA-4) can provoke T cell-dependent antitumor activity that generates durable clinical responses in some patients. The epigenetic and transcriptional features that T cells require for efficacious ICT remain to be fully elucidated. Herein, we report that anti-PD-1 and anti-CTLA-4 ICT induce upregulation of the transcription factor BHLHE40 in tumor antigen-specific CD8+ and CD4+ T cells and that T cells require BHLHE40 for effective ICT in mice bearing immune-edited tumors. Single-cell RNA sequencing of intratumoral immune cells in BHLHE40-deficient mice revealed differential ICT-induced immune cell remodeling. The BHLHE40-dependent gene expression changes indicated dysregulated metabolism, NF-κB signaling, and IFNγ response within certain subpopulations of CD4+ and CD8+ T cells. Intratumoral CD4+ and CD8+ T cells from BHLHE40-deficient mice exhibited higher expression of the inhibitory receptor gene Tigit and displayed alterations in expression of genes encoding chemokines/chemokine receptors and granzyme family members. Mice lacking BHLHE40 had reduced ICT-driven IFNγ production by CD4+ and CD8+ T cells and defects in ICT-induced remodeling of macrophages from a CX3CR1+CD206+ subpopulation to an iNOS+ subpopulation that is typically observed during effective ICT. Although both anti-PD-1 and anti-CTLA-4 ICT in BHLHE40-deficient mice led to the same outcome-tumor outgrowth-several BHLHE40-dependent alterations were specific to the ICT that was used. Our results reveal a crucial role for BHLHE40 in effective ICT and suggest that BHLHE40 may be a predictive or prognostic biomarker for ICT efficacy and a potential therapeutic target. (©2022 The Authors; Published by the American Association for Cancer Research.)
Databáze:	MEDLINE
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