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BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy
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 fea...
Autores principales: | , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
American Association for Cancer Research
2022
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164498/ https://www.ncbi.nlm.nih.gov/pubmed/35181783 http://dx.doi.org/10.1158/2326-6066.CIR-21-0129 |
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author | Salmon, Avery J. Shavkunov, Alexander S. Miao, Qi Jarjour, Nicholas N. Keshari, Sunita Esaulova, Ekaterina Williams, Charmelle D. Ward, Jeffrey P. Highsmith, Anna M. Pineda, Josué E. Taneja, Reshma Chen, Ken Edelson, Brian T. Gubin, Matthew M. |
author_facet | Salmon, Avery J. Shavkunov, Alexander S. Miao, Qi Jarjour, Nicholas N. Keshari, Sunita Esaulova, Ekaterina Williams, Charmelle D. Ward, Jeffrey P. Highsmith, Anna M. Pineda, Josué E. Taneja, Reshma Chen, Ken Edelson, Brian T. Gubin, Matthew M. |
author_sort | Salmon, Avery J. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-9164498 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2022 |
publisher | American Association for Cancer Research |
record_format | MEDLINE/PubMed |
spelling | pubmed-91644982022-11-03 BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy Salmon, Avery J. Shavkunov, Alexander S. Miao, Qi Jarjour, Nicholas N. Keshari, Sunita Esaulova, Ekaterina Williams, Charmelle D. Ward, Jeffrey P. Highsmith, Anna M. Pineda, Josué E. Taneja, Reshma Chen, Ken Edelson, Brian T. Gubin, Matthew M. Cancer Immunol Res Research Articles 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. American Association for Cancer Research 2022-05-03 2022-02-18 /pmc/articles/PMC9164498/ /pubmed/35181783 http://dx.doi.org/10.1158/2326-6066.CIR-21-0129 Text en ©2022 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
spellingShingle | Research Articles Salmon, Avery J. Shavkunov, Alexander S. Miao, Qi Jarjour, Nicholas N. Keshari, Sunita Esaulova, Ekaterina Williams, Charmelle D. Ward, Jeffrey P. Highsmith, Anna M. Pineda, Josué E. Taneja, Reshma Chen, Ken Edelson, Brian T. Gubin, Matthew M. BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy |
title | BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy |
title_full | BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy |
title_fullStr | BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy |
title_full_unstemmed | BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy |
title_short | BHLHE40 Regulates the T-Cell Effector Function Required for Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy |
title_sort | bhlhe40 regulates the t-cell effector function required for tumor microenvironment remodeling and immune checkpoint therapy efficacy |
topic | Research Articles |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9164498/ https://www.ncbi.nlm.nih.gov/pubmed/35181783 http://dx.doi.org/10.1158/2326-6066.CIR-21-0129 |
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