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Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer

The implementation of cancer immunotherapeutics for solid tumors including lung cancers has improved clinical outcomes in a small percentage of patients. However, the majority of patients show little to no response or acquire resistance during treatment with checkpoint inhibitors delivered as a mono...

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Autores principales: Konen, Jessica M., Rodriguez, B. Leticia, Fradette, Jared J., Gibson, Laura, Davis, Denali, Minelli, Rosalba, Peoples, Michael D., Kovacs, Jeffrey, Carugo, Alessandro, Bristow, Christopher, Heffernan, Timothy, Gibbons, Don L.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2019
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521201/
https://www.ncbi.nlm.nih.gov/pubmed/30986992
http://dx.doi.org/10.3390/cancers11040462
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author Konen, Jessica M.
Rodriguez, B. Leticia
Fradette, Jared J.
Gibson, Laura
Davis, Denali
Minelli, Rosalba
Peoples, Michael D.
Kovacs, Jeffrey
Carugo, Alessandro
Bristow, Christopher
Heffernan, Timothy
Gibbons, Don L.
author_facet Konen, Jessica M.
Rodriguez, B. Leticia
Fradette, Jared J.
Gibson, Laura
Davis, Denali
Minelli, Rosalba
Peoples, Michael D.
Kovacs, Jeffrey
Carugo, Alessandro
Bristow, Christopher
Heffernan, Timothy
Gibbons, Don L.
author_sort Konen, Jessica M.
collection PubMed
description The implementation of cancer immunotherapeutics for solid tumors including lung cancers has improved clinical outcomes in a small percentage of patients. However, the majority of patients show little to no response or acquire resistance during treatment with checkpoint inhibitors delivered as a monotherapy. Therefore, identifying resistance mechanisms and novel combination therapy approaches is imperative to improve responses to immune checkpoint inhibitors. To address this, we performed an in vivo shRNA dropout screen that focused on genes encoding for FDA-approved drug targets (FDAome). We implanted epithelial and mesenchymal Kras/p53 (KP) mutant murine lung cancer cells expressing the FDAome shRNA library into syngeneic mice treated with an anti-PD-1 antibody. Sequencing for the barcoded shRNAs revealed Ntrk1 was significantly depleted from mesenchymal tumors challenged with PD-1 blockade, suggesting it provides a survival advantage to tumor cells when under immune system pressure. Our data confirmed Ntrk1 transcript levels are upregulated in tumors treated with PD-1 inhibitors. Additionally, analysis of tumor-infiltrating T cell populations revealed that Ntrk1 can promote CD8+ T cell exhaustion. Lastly, we found that Ntrk1 regulates Jak/Stat signaling to promote expression of PD-L1 on tumor cells. Together, these data suggest that Ntrk1 activates Jak/Stat signaling to regulate expression of immunosuppressive molecules including PD-L1, promoting exhaustion within the tumor microenvironment.
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spelling pubmed-65212012019-05-31 Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer Konen, Jessica M. Rodriguez, B. Leticia Fradette, Jared J. Gibson, Laura Davis, Denali Minelli, Rosalba Peoples, Michael D. Kovacs, Jeffrey Carugo, Alessandro Bristow, Christopher Heffernan, Timothy Gibbons, Don L. Cancers (Basel) Article The implementation of cancer immunotherapeutics for solid tumors including lung cancers has improved clinical outcomes in a small percentage of patients. However, the majority of patients show little to no response or acquire resistance during treatment with checkpoint inhibitors delivered as a monotherapy. Therefore, identifying resistance mechanisms and novel combination therapy approaches is imperative to improve responses to immune checkpoint inhibitors. To address this, we performed an in vivo shRNA dropout screen that focused on genes encoding for FDA-approved drug targets (FDAome). We implanted epithelial and mesenchymal Kras/p53 (KP) mutant murine lung cancer cells expressing the FDAome shRNA library into syngeneic mice treated with an anti-PD-1 antibody. Sequencing for the barcoded shRNAs revealed Ntrk1 was significantly depleted from mesenchymal tumors challenged with PD-1 blockade, suggesting it provides a survival advantage to tumor cells when under immune system pressure. Our data confirmed Ntrk1 transcript levels are upregulated in tumors treated with PD-1 inhibitors. Additionally, analysis of tumor-infiltrating T cell populations revealed that Ntrk1 can promote CD8+ T cell exhaustion. Lastly, we found that Ntrk1 regulates Jak/Stat signaling to promote expression of PD-L1 on tumor cells. Together, these data suggest that Ntrk1 activates Jak/Stat signaling to regulate expression of immunosuppressive molecules including PD-L1, promoting exhaustion within the tumor microenvironment. MDPI 2019-04-02 /pmc/articles/PMC6521201/ /pubmed/30986992 http://dx.doi.org/10.3390/cancers11040462 Text en © 2019 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Konen, Jessica M.
Rodriguez, B. Leticia
Fradette, Jared J.
Gibson, Laura
Davis, Denali
Minelli, Rosalba
Peoples, Michael D.
Kovacs, Jeffrey
Carugo, Alessandro
Bristow, Christopher
Heffernan, Timothy
Gibbons, Don L.
Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer
title Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer
title_full Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer
title_fullStr Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer
title_full_unstemmed Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer
title_short Ntrk1 Promotes Resistance to PD-1 Checkpoint Blockade in Mesenchymal Kras/p53 Mutant Lung Cancer
title_sort ntrk1 promotes resistance to pd-1 checkpoint blockade in mesenchymal kras/p53 mutant lung cancer
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6521201/
https://www.ncbi.nlm.nih.gov/pubmed/30986992
http://dx.doi.org/10.3390/cancers11040462
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