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RETRACTED ARTICLE: A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function

Overcoming tumor-mediated immunosuppression and enhancing cytotoxic T-cell activity within the tumor microenvironment are two central goals of immuno-oncology (IO) drug discovery initiatives. However, exploratory assays involving immune components are often plagued by low-throughput and poor clinica...

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Autores principales: To, Jeremy, Quackenbush, Doug, Rowell, Emily, Li, Lilin, Reed, Connor, Lo, Frederick, Horman, Shane R.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Nature Publishing Group UK 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794535/
https://www.ncbi.nlm.nih.gov/pubmed/33420321
http://dx.doi.org/10.1038/s42003-020-01565-1
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author To, Jeremy
Quackenbush, Doug
Rowell, Emily
Li, Lilin
Reed, Connor
Lo, Frederick
Horman, Shane R.
author_facet To, Jeremy
Quackenbush, Doug
Rowell, Emily
Li, Lilin
Reed, Connor
Lo, Frederick
Horman, Shane R.
author_sort To, Jeremy
collection PubMed
description Overcoming tumor-mediated immunosuppression and enhancing cytotoxic T-cell activity within the tumor microenvironment are two central goals of immuno-oncology (IO) drug discovery initiatives. However, exploratory assays involving immune components are often plagued by low-throughput and poor clinical relevance. Here we present an innovative ultra-high-content assay platform for interrogating T-cell-mediated killing of 3D multicellular tumor spheroids. Employing this assay platform in a chemical genomics screen of 1800 annotated compounds enabled identification of small molecule perturbagens capable of enhancing cytotoxic CD8(+) T-cell activity in an antigen-dependent manner. Specifically, cyclin-dependent kinase (CDK) and bromodomain (BRD) protein inhibitors were shown to significantly augment anti-tumor T-cell function by increasing cytolytic granule and type II interferon secretion in T-cells in addition to upregulating major histocompatibility complex (MHC) expression and antigen presentation in tumor cells. The described biotechnology screening platform yields multi-parametric, clinically-relevant data and can be employed kinetically for the discovery of first-in-class IO therapeutic agents.
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spelling pubmed-77945352021-01-21 RETRACTED ARTICLE: A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function To, Jeremy Quackenbush, Doug Rowell, Emily Li, Lilin Reed, Connor Lo, Frederick Horman, Shane R. Commun Biol Article Overcoming tumor-mediated immunosuppression and enhancing cytotoxic T-cell activity within the tumor microenvironment are two central goals of immuno-oncology (IO) drug discovery initiatives. However, exploratory assays involving immune components are often plagued by low-throughput and poor clinical relevance. Here we present an innovative ultra-high-content assay platform for interrogating T-cell-mediated killing of 3D multicellular tumor spheroids. Employing this assay platform in a chemical genomics screen of 1800 annotated compounds enabled identification of small molecule perturbagens capable of enhancing cytotoxic CD8(+) T-cell activity in an antigen-dependent manner. Specifically, cyclin-dependent kinase (CDK) and bromodomain (BRD) protein inhibitors were shown to significantly augment anti-tumor T-cell function by increasing cytolytic granule and type II interferon secretion in T-cells in addition to upregulating major histocompatibility complex (MHC) expression and antigen presentation in tumor cells. The described biotechnology screening platform yields multi-parametric, clinically-relevant data and can be employed kinetically for the discovery of first-in-class IO therapeutic agents. Nature Publishing Group UK 2021-01-08 /pmc/articles/PMC7794535/ /pubmed/33420321 http://dx.doi.org/10.1038/s42003-020-01565-1 Text en © The Author(s) 2021 https://creativecommons.org/licenses/by/4.0/Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons license, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons license and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this license, visit http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) .
spellingShingle Article
To, Jeremy
Quackenbush, Doug
Rowell, Emily
Li, Lilin
Reed, Connor
Lo, Frederick
Horman, Shane R.
RETRACTED ARTICLE: A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function
title RETRACTED ARTICLE: A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function
title_full RETRACTED ARTICLE: A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function
title_fullStr RETRACTED ARTICLE: A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function
title_full_unstemmed RETRACTED ARTICLE: A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function
title_short RETRACTED ARTICLE: A biomimetic assay platform for the interrogation of antigen-dependent anti-tumor T-cell function
title_sort retracted article: a biomimetic assay platform for the interrogation of antigen-dependent anti-tumor t-cell function
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7794535/
https://www.ncbi.nlm.nih.gov/pubmed/33420321
http://dx.doi.org/10.1038/s42003-020-01565-1
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