Advancements in immunotherapy treatments have become essential in the treatment of various cancers, such as those with high tumor burden like melanoma(Brahmer et al., 2012; Hodi et al., 2010). Immunotherapy, specifically immune checkpoint therapy (ICT) provides antagonist effect on specific immune checkpoints to control effector T cell functions(Pardoll, 2012). This therapy allows for the modulation of anti-tumor responses through the use of monoclonal antibodies, such as anti-CTLA-4 or anti-PD-1 that block the receptors from binding with their ligands, thus allowing for CD4+ and CD8+ T cell priming and activation(Wei et al., 2017). However, the required epigenetic and transcriptional features that T cells must possess to efficaciously respond to ICT remains unclear. We show the transcription factor BHLHE40 is required in T cells for effective ICT response in mice bearing immune-edited tumors. Furthermore, we show BHLHE40 is upregulated in tumor antigen-specific CD8+ and CD4+ T cells upon ICT treatment with anti-CTLA-4 or anti-PD-1. Using single-cell RNA sequencing (scRNAseq), we revealed ICT-induced immune compartment remodeling in intratumoral immune cells taken from BHLHE40-deficent mice.
These BHLHE40-dependent gene expression changes indicated dysregulated metabolism, NF-kB signaling, and IFNg response within certain subpopulations of CD4+ and CD8+ T cells. Intratumoral CD4+ and CD8+ T cells from BHLHE40-deficient mice also exhibited higher expression of the inhibitory receptor gene Tigit and displayed alterations in chemokine/chemokine receptor gene expression with altered gene expression of granzyme family members. Mice lacking BHLHE40 had reduced ICT-driven IFNg 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 lead to 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.
","abstract_html":"<p>Advancements in immunotherapy treatments have become essential in the treatment of various cancers, such as those with high tumor burden like melanoma(Brahmer et al., 2012; Hodi et al., 2010). Immunotherapy, specifically immune checkpoint therapy (ICT) provides antagonist effect on specific immune checkpoints to control effector T cell functions(Pardoll, 2012). This therapy allows for the modulation of anti-tumor responses through the use of monoclonal antibodies, such as anti-CTLA-4 or anti-PD-1 that block the receptors from binding with their ligands, thus allowing for CD4<sup>+</sup> and CD8<sup>+</sup> T cell priming and activation(Wei et al., 2017). However, the required epigenetic and transcriptional features that T cells must possess to efficaciously respond to ICT remains unclear. We show the transcription factor BHLHE40 is required in T cells for effective ICT response in mice bearing immune-edited tumors. Furthermore, we show BHLHE40 is upregulated in tumor antigen-specific CD8<sup>+</sup> and CD4<sup>+</sup> T cells upon ICT treatment with anti-CTLA-4 or anti-PD-1. Using single-cell RNA sequencing (scRNAseq), we revealed ICT-induced immune compartment remodeling in intratumoral immune cells taken from BHLHE40-deficent mice.</p> <p>These BHLHE40-dependent gene expression changes indicated dysregulated metabolism, NF-kB signaling, and IFNg response within certain subpopulations of CD4<sup>+</sup> and CD8<sup>+</sup> T cells. Intratumoral CD4<sup>+</sup> and CD8<sup>+</sup> T cells from BHLHE40-deficient mice also exhibited higher expression of the inhibitory receptor gene <em>Tigit</em> and displayed alterations in chemokine/chemokine receptor gene expression with altered gene expression of granzyme family members. Mice lacking BHLHE40 had reduced ICT-driven IFNg production by CD4<sup>+</sup> and CD8<sup>+</sup> T cells and defects in ICT-induced remodeling of macrophages from a CX3CR1<sup>+ </sup>CD206<sup>+</sup> subpopulation to an iNOS<sup>+</sup> subpopulation that is typically observed during effective ICT. Although both anti-PD-1 and anti-CTLA-4 ICT in BHLHE40-deficient mice lead to 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.</p>","abstract_has_math":false,"creators":["Salmon, Avery","Salmon, Avery J","https://orcid.org/0000-0003-3470-0921
"],"institution":null,"degree_name":"Masters of Science (MS)","degree_level":"Thesis (MS)","degree_discipline":null,"degree_department":null,"school":null,"contributors":["Matthew Gubin","Stephanie Watowich","Michael Curran"],"advisors":[],"committee_chairs":[],"committee_members":[],"year":2022,"date_issued":"2022-08-01T07:00:00Z","date_published":"2022-08-01T07:00:00Z","updated_at":"2026-07-24T05:50:38Z","subjects":["BHLHE40","ICT","anti-CTLA-4","anti-PD-1","scRNAseq","biomarker","Biological Phenomena, Cell Phenomena, and Immunity","Translational Medical Research"],"languages":[],"rights":[],"rights_urls":[],"identifier_entries":[]},"links":{"outbound_url":"https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1207","outbound_label":"Repository record","outbound_source":"dc:identifier"},"metadata_groups":[{"id":"people","label":"People","entries":[{"key":"dc:contributor","label":"Contributor","values":["Matthew Gubin","Stephanie Watowich","Michael Curran"]},{"key":"dc:creator","label":"Author","values":["Salmon, Avery","Salmon, Avery J","https://orcid.org/0000-0003-3470-0921
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These BHLHE40-dependent gene expression changes indicated dysregulated metabolism, NF-kB signaling, and IFNg response within certain subpopulations of CD4+ and CD8+ T cells. Intratumoral CD4+ and CD8+ T cells from BHLHE40-deficient mice also exhibited higher expression of the inhibitory receptor gene Tigit and displayed alterations in chemokine/chemokine receptor gene expression with altered gene expression of granzyme family members. Mice lacking BHLHE40 had reduced ICT-driven IFNg 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 lead to 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.
"]},{"key":"dc:title","label":"Title","values":["Bhlhe40: Required For Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy"]}]}],"canonical_facts":{"dc:contributor":["Matthew Gubin","Stephanie Watowich","Michael Curran"],"dc:creator":["Salmon, Avery","Salmon, Avery J","https://orcid.org/0000-0003-3470-0921
"],"dc:date.available":["2022-08-02T07:00:00Z"],"dc:description.abstract":["Advancements in immunotherapy treatments have become essential in the treatment of various cancers, such as those with high tumor burden like melanoma(Brahmer et al., 2012; Hodi et al., 2010). Immunotherapy, specifically immune checkpoint therapy (ICT) provides antagonist effect on specific immune checkpoints to control effector T cell functions(Pardoll, 2012). This therapy allows for the modulation of anti-tumor responses through the use of monoclonal antibodies, such as anti-CTLA-4 or anti-PD-1 that block the receptors from binding with their ligands, thus allowing for CD4+ and CD8+ T cell priming and activation(Wei et al., 2017). However, the required epigenetic and transcriptional features that T cells must possess to efficaciously respond to ICT remains unclear. We show the transcription factor BHLHE40 is required in T cells for effective ICT response in mice bearing immune-edited tumors. Furthermore, we show BHLHE40 is upregulated in tumor antigen-specific CD8+ and CD4+ T cells upon ICT treatment with anti-CTLA-4 or anti-PD-1. Using single-cell RNA sequencing (scRNAseq), we revealed ICT-induced immune compartment remodeling in intratumoral immune cells taken from BHLHE40-deficent mice.
These BHLHE40-dependent gene expression changes indicated dysregulated metabolism, NF-kB signaling, and IFNg response within certain subpopulations of CD4+ and CD8+ T cells. Intratumoral CD4+ and CD8+ T cells from BHLHE40-deficient mice also exhibited higher expression of the inhibitory receptor gene Tigit and displayed alterations in chemokine/chemokine receptor gene expression with altered gene expression of granzyme family members. Mice lacking BHLHE40 had reduced ICT-driven IFNg 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 lead to 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.
"],"dc:identifier":["https://digitalcommons.library.tmc.edu/utgsbs_dissertations/1207"],"dc:subject":["BHLHE40","ICT","anti-CTLA-4","anti-PD-1","scRNAseq","biomarker","Biological Phenomena, Cell Phenomena, and Immunity","Translational Medical Research"],"dc:title":["Bhlhe40: Required For Tumor Microenvironment Remodeling and Immune Checkpoint Therapy Efficacy"],"thesis:degree_level":["Thesis (MS)"],"thesis:degree_name":["Masters of Science (MS)"]},"updated_at":"2026-07-24T05:50:38Z"}