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

Overview of attention for article published in Cancer Immunology Research, February 2022
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  • In the top 5% of all research outputs scored by Altmetric
  • High Attention Score compared to outputs of the same age (94th percentile)
  • High Attention Score compared to outputs of the same age and source (96th percentile)

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4 news outlets
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Title
BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy
Published in
Cancer Immunology Research, February 2022
DOI 10.1158/2326-6066.cir-21-0129
Pubmed ID
Authors

Avery J. Salmon, Alexander S. Shavkunov, Qi Miao, Nicholas N. Jarjour, Sunita Keshari, Ekaterina Esaulova, Charmelle D. Williams, Jeffrey P. Ward, Anna M. Highsmith, Josué E. Pineda, Reshma Taneja, Ken Chen, Brian T. Edelson, Matthew M. Gubin

Abstract

Immune checkpoint therapy (ICT) using antibody blockade of PD-1 or 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 IFN-γ 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 chemokine/chemokine receptors and granzyme family members. Mice lacking BHLHE40 had reduced ICT-driven IFN-γ 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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Attention Score in Context

This research output has an Altmetric Attention Score of 39. This is our high-level measure of the quality and quantity of online attention that it has received. This Attention Score, as well as the ranking and number of research outputs shown below, was calculated when the research output was last mentioned on 19 May 2022.
All research outputs
#794,678
of 21,217,760 outputs
Outputs from Cancer Immunology Research
#82
of 1,261 outputs
Outputs of similar age
#18,321
of 331,775 outputs
Outputs of similar age from Cancer Immunology Research
#2
of 25 outputs
Altmetric has tracked 21,217,760 research outputs across all sources so far. Compared to these this one has done particularly well and is in the 96th percentile: it's in the top 5% of all research outputs ever tracked by Altmetric.
So far Altmetric has tracked 1,261 research outputs from this source. They typically receive a lot more attention than average, with a mean Attention Score of 10.7. This one has done particularly well, scoring higher than 93% of its peers.
Older research outputs will score higher simply because they've had more time to accumulate mentions. To account for age we can compare this Altmetric Attention Score to the 331,775 tracked outputs that were published within six weeks on either side of this one in any source. This one has done particularly well, scoring higher than 94% of its contemporaries.
We're also able to compare this research output to 25 others from the same source and published within six weeks on either side of this one. This one has done particularly well, scoring higher than 96% of its contemporaries.