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

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Affiliations

  • 1. Department of Immunology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
      Authors
    • Salmon AJ 1
    • Shavkunov AS 1
    • Keshari S 1
    • Williams CD 1
    • Highsmith AM 1
    • Pineda JE 1
    • Gubin MM 1
    (7 authors)
  • 2. Department of Bioinformatics and Computational Biology, The University of Texas MD Anderson Cancer Center, Houston, Texas.
      Authors
    • Miao Q 2
    • Chen K 2
    (2 authors)
  • 3. Department of Pathology and Immunology, Washington University School of Medicine, St. Louis, Missouri.
      Authors
    • Jarjour NN 3
    • Esaulova E 3
    • Edelson BT 3
    (3 authors)
  • 4. Division of Oncology, Department of Medicine, Washington University School of Medicine, St. Louis, Missouri.
      Authors
    • Ward JP 4
    (1 author)
  • 5. Department of Physiology, Healthy Longevity Translation Research Program, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, Singapore.
      Authors
    • Taneja R 5
    (1 author)

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Cancer Immunology Research, 01 May 2022, 10(5):597-611
https://doi.org/10.1158/2326-6066.cir-21-0129 PMID: 35181783 PMCID: PMC9164498

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Abstract 

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.

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Read article at publisher's site: https://doi.org/10.1158/2326-6066.cir-21-0129

Read article for free, from open access legal sources, via Unpaywall: https://aacrjournals.org/cancerimmunolres/article-pdf/10/5/597/3191681/597.pdfUnpaywall

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Funding 

Funders who supported this work.

CPRIT (1)

Damon Runyon Cancer Research Foundation (1)

NCI (1)

NCI Cancer Center (1)

NCI NIH (1)

NCI NIH Cancer Center (1)

NCI NIH HHS (5)

NIAID NIH HHS (2)

NIH (1)

NIH HHS (1)

NIH NCI (4)