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A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells

INTRODUCTION: Significant heterogeneity exists within the tumor-infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and may retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the...

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Autores principales: Cameron, Cheryl M., Richardson, Brian, Golden, Jackelyn B., Phoon, Yee Peng, Tamilselvan, Banumathi, Pfannenstiel, Lukas, Thapaliya, Samjhana, Roversi, Gustavo, Gao, Xing-Huang, Zagore, Leah L., Cameron, Mark J., Gastman, Brian R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643547/
https://www.ncbi.nlm.nih.gov/pubmed/38023136
http://dx.doi.org/10.3389/fonc.2023.1200387
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author Cameron, Cheryl M.
Richardson, Brian
Golden, Jackelyn B.
Phoon, Yee Peng
Tamilselvan, Banumathi
Pfannenstiel, Lukas
Thapaliya, Samjhana
Roversi, Gustavo
Gao, Xing-Huang
Zagore, Leah L.
Cameron, Mark J.
Gastman, Brian R.
author_facet Cameron, Cheryl M.
Richardson, Brian
Golden, Jackelyn B.
Phoon, Yee Peng
Tamilselvan, Banumathi
Pfannenstiel, Lukas
Thapaliya, Samjhana
Roversi, Gustavo
Gao, Xing-Huang
Zagore, Leah L.
Cameron, Mark J.
Gastman, Brian R.
author_sort Cameron, Cheryl M.
collection PubMed
description INTRODUCTION: Significant heterogeneity exists within the tumor-infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and may retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the tumor microenvironment is associated with poor cancer outcomes, making exploration of these exhausted T cell subpopulations critical to the improvement of therapeutic approaches. METHODS: To investigate mechanisms associated with terminally exhausted T cells, we sorted and performed transcriptional profiling of CD8(+) tumor-infiltrating lymphocytes (TILs) co-expressing the exhaustion markers PD-1 and TIM-3 from large-volume melanoma tumors. We additionally performed immunologic phenotyping and functional validation, including at the single-cell level, to identify potential mechanisms that underlie their dysfunctional phenotype. RESULTS: We identified novel dysregulated pathways in CD8(+)PD-1(+)TIM-3(+) cells that have not been well studied in TILs; these include bile acid and peroxisome pathway-related metabolism and mammalian target of rapamycin (mTOR) signaling pathways, which are highly correlated with immune checkpoint receptor expression. DISCUSSION: Based on bioinformatic integration of immunophenotypic data and network analysis, we propose unexpected targets for therapies to rescue the immune response to tumors in melanoma.
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spelling pubmed-106435472023-01-01 A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells Cameron, Cheryl M. Richardson, Brian Golden, Jackelyn B. Phoon, Yee Peng Tamilselvan, Banumathi Pfannenstiel, Lukas Thapaliya, Samjhana Roversi, Gustavo Gao, Xing-Huang Zagore, Leah L. Cameron, Mark J. Gastman, Brian R. Front Oncol Oncology INTRODUCTION: Significant heterogeneity exists within the tumor-infiltrating CD8 T cell population, and exhausted T cells harbor a subpopulation that may be replicating and may retain signatures of activation, with potential functional consequences in tumor progression. Dysfunctional immunity in the tumor microenvironment is associated with poor cancer outcomes, making exploration of these exhausted T cell subpopulations critical to the improvement of therapeutic approaches. METHODS: To investigate mechanisms associated with terminally exhausted T cells, we sorted and performed transcriptional profiling of CD8(+) tumor-infiltrating lymphocytes (TILs) co-expressing the exhaustion markers PD-1 and TIM-3 from large-volume melanoma tumors. We additionally performed immunologic phenotyping and functional validation, including at the single-cell level, to identify potential mechanisms that underlie their dysfunctional phenotype. RESULTS: We identified novel dysregulated pathways in CD8(+)PD-1(+)TIM-3(+) cells that have not been well studied in TILs; these include bile acid and peroxisome pathway-related metabolism and mammalian target of rapamycin (mTOR) signaling pathways, which are highly correlated with immune checkpoint receptor expression. DISCUSSION: Based on bioinformatic integration of immunophenotypic data and network analysis, we propose unexpected targets for therapies to rescue the immune response to tumors in melanoma. Frontiers Media S.A. 2023-10-30 /pmc/articles/PMC10643547/ /pubmed/38023136 http://dx.doi.org/10.3389/fonc.2023.1200387 Text en Copyright © 2023 Cameron, Richardson, Golden, Phoon, Tamilselvan, Pfannenstiel, Thapaliya, Roversi, Gao, Zagore, Cameron and Gastman https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Oncology
Cameron, Cheryl M.
Richardson, Brian
Golden, Jackelyn B.
Phoon, Yee Peng
Tamilselvan, Banumathi
Pfannenstiel, Lukas
Thapaliya, Samjhana
Roversi, Gustavo
Gao, Xing-Huang
Zagore, Leah L.
Cameron, Mark J.
Gastman, Brian R.
A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells
title A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells
title_full A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells
title_fullStr A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells
title_full_unstemmed A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells
title_short A transcriptional evaluation of the melanoma and squamous cell carcinoma TIL compartment reveals an unexpected spectrum of exhausted and functional T cells
title_sort transcriptional evaluation of the melanoma and squamous cell carcinoma til compartment reveals an unexpected spectrum of exhausted and functional t cells
topic Oncology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10643547/
https://www.ncbi.nlm.nih.gov/pubmed/38023136
http://dx.doi.org/10.3389/fonc.2023.1200387
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