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TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model

Immune checkpoint inhibitors have demonstrated, over the recent years, impressive clinical response in cancer patients, but some patients do not respond at all to checkpoint blockade, exhibiting primary resistance. Primary resistance to PD-1 blockade is reported to occur under conditions of immunosu...

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Detalles Bibliográficos
Autores principales: Siewe, Nourridine, Friedman, Avner
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168900/
https://www.ncbi.nlm.nih.gov/pubmed/34061898
http://dx.doi.org/10.1371/journal.pone.0252620
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author Siewe, Nourridine
Friedman, Avner
author_facet Siewe, Nourridine
Friedman, Avner
author_sort Siewe, Nourridine
collection PubMed
description Immune checkpoint inhibitors have demonstrated, over the recent years, impressive clinical response in cancer patients, but some patients do not respond at all to checkpoint blockade, exhibiting primary resistance. Primary resistance to PD-1 blockade is reported to occur under conditions of immunosuppressive tumor environment, a condition caused by myeloid derived suppressor cells (MDSCs), and by T cells exclusion, due to increased level of T regulatory cells (Tregs). Since TGF-β activates Tregs, TGF-β inhibitor may overcome primary resistance to anti-PD-1. Indeed, recent mice experiments show that combining anti-PD-1 with anti-TGF-β yields significant therapeutic improvements compared to anti-TGF-β alone. The present paper introduces two cancer-specific parameters and, correspondingly, develops a mathematical model which explains how primary resistance to PD-1 blockade occurs, in terms of the two cancer-specific parameters, and how, in combination with anti-TGF-β, anti-PD-1 provides significant benefits. The model is represented by a system of partial differential equations and the simulations are in agreement with the recent mice experiments. In some cancer patients, treatment with anti-PD-1 results in rapid progression of the disease, known as hyperprogression disease (HPD). The mathematical model can also explain how this situation arises, and it predicts that HPD may be reversed by combining anti-TGF-β to anti-PD-1. The model is used to demonstrate how the two cancer-specific parameters may serve as biomarkers in predicting the efficacy of combination therapy with PD-1 and TGF-β inhibitors.
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spelling pubmed-81689002021-06-11 TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model Siewe, Nourridine Friedman, Avner PLoS One Research Article Immune checkpoint inhibitors have demonstrated, over the recent years, impressive clinical response in cancer patients, but some patients do not respond at all to checkpoint blockade, exhibiting primary resistance. Primary resistance to PD-1 blockade is reported to occur under conditions of immunosuppressive tumor environment, a condition caused by myeloid derived suppressor cells (MDSCs), and by T cells exclusion, due to increased level of T regulatory cells (Tregs). Since TGF-β activates Tregs, TGF-β inhibitor may overcome primary resistance to anti-PD-1. Indeed, recent mice experiments show that combining anti-PD-1 with anti-TGF-β yields significant therapeutic improvements compared to anti-TGF-β alone. The present paper introduces two cancer-specific parameters and, correspondingly, develops a mathematical model which explains how primary resistance to PD-1 blockade occurs, in terms of the two cancer-specific parameters, and how, in combination with anti-TGF-β, anti-PD-1 provides significant benefits. The model is represented by a system of partial differential equations and the simulations are in agreement with the recent mice experiments. In some cancer patients, treatment with anti-PD-1 results in rapid progression of the disease, known as hyperprogression disease (HPD). The mathematical model can also explain how this situation arises, and it predicts that HPD may be reversed by combining anti-TGF-β to anti-PD-1. The model is used to demonstrate how the two cancer-specific parameters may serve as biomarkers in predicting the efficacy of combination therapy with PD-1 and TGF-β inhibitors. Public Library of Science 2021-06-01 /pmc/articles/PMC8168900/ /pubmed/34061898 http://dx.doi.org/10.1371/journal.pone.0252620 Text en © 2021 Siewe, Friedman https://creativecommons.org/licenses/by/4.0/This is an open access article distributed under the terms of the Creative Commons Attribution License (https://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Siewe, Nourridine
Friedman, Avner
TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model
title TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model
title_full TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model
title_fullStr TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model
title_full_unstemmed TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model
title_short TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model
title_sort tgf-β inhibition can overcome cancer primary resistance to pd-1 blockade: a mathematical model
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8168900/
https://www.ncbi.nlm.nih.gov/pubmed/34061898
http://dx.doi.org/10.1371/journal.pone.0252620
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