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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Autores principales:	Nourridine Siewe, Avner Friedman
Formato:	article
Lenguaje:	EN
Publicado:	Public Library of Science (PLoS) 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/7dca81abbfbf4d83b65009791af3b7f8
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spelling	oai:doaj.org-article:7dca81abbfbf4d83b65009791af3b7f82021-12-02T20:11:10ZTGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model.1932-620310.1371/journal.pone.0252620https://doaj.org/article/7dca81abbfbf4d83b65009791af3b7f82021-01-01T00:00:00Zhttps://doi.org/10.1371/journal.pone.0252620https://doaj.org/toc/1932-6203Immune 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.Nourridine SieweAvner FriedmanPublic Library of Science (PLoS)articleMedicineRScienceQENPLoS ONE, Vol 16, Iss 6, p e0252620 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Nourridine Siewe Avner Friedman TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model.
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.
format	article
author	Nourridine Siewe Avner Friedman
author_facet	Nourridine Siewe Avner Friedman
author_sort	Nourridine Siewe
title	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_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_sort	tgf-β inhibition can overcome cancer primary resistance to pd-1 blockade: a mathematical model.
publisher	Public Library of Science (PLoS)
publishDate	2021
url	https://doaj.org/article/7dca81abbfbf4d83b65009791af3b7f8
work_keys_str_mv	AT nourridinesiewe tgfbinhibitioncanovercomecancerprimaryresistancetopd1blockadeamathematicalmodel AT avnerfriedman tgfbinhibitioncanovercomecancerprimaryresistancetopd1blockadeamathematicalmodel
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TGF-β inhibition can overcome cancer primary resistance to PD-1 blockade: A mathematical model.

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