Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy

Programmed cell death-1 (PD-1) blockade has a profound effect on the ability of the immune system to eliminate tumors, but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following i...

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Autores principales:	Sukanya Raghavan, Nataliya Tovbis-Shifrin, Christina Kochel, Anandi Sawant, Marielle Mello, Manjiri Sathe, Wendy Blumenschein, Eric S. Muise, Alissa Chackerian, Elaine M. Pinheiro, Thomas W. Rosahl, Hervé Luche, Rene de Waal Malefyt
Formato:	article
Lenguaje:	EN
Publicado:	Frontiers Media S.A. 2021
Materias:	conditional KO mice IFN gamma PD-1 mass cytometry (CyTOF) tumor immunity and immunotherapy CD8 T cell Immunologic diseases. Allergy RC581-607
Acceso en línea:	https://doaj.org/article/72fd7ab5d05749e780b38e08a7d4a277
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spelling	oai:doaj.org-article:72fd7ab5d05749e780b38e08a7d4a2772021-12-01T13:27:50ZConditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy1664-322410.3389/fimmu.2021.752348https://doaj.org/article/72fd7ab5d05749e780b38e08a7d4a2772021-11-01T00:00:00Zhttps://www.frontiersin.org/articles/10.3389/fimmu.2021.752348/fullhttps://doaj.org/toc/1664-3224Programmed cell death-1 (PD-1) blockade has a profound effect on the ability of the immune system to eliminate tumors, but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) mice and in wild-type mice treated with PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor-infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 20-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All five subsets expressed granzyme B and interferon gamma (IFNγ). Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO- and PD-1 Ab-treated mice and showed an upregulation of pathways related to CD4 and CD8 T-cell activation, enhanced signaling through costimulatory molecules and IFNγ, and non-T-cell processes. Altogether, using PD-1cKO mice, we define the intrinsic nature of PD-1 suppression of CD8 T-cell responses in tumor immunity.Sukanya RaghavanSukanya RaghavanNataliya Tovbis-ShifrinChristina KochelAnandi SawantMarielle MelloManjiri SatheWendy BlumenscheinEric S. MuiseAlissa ChackerianElaine M. PinheiroThomas W. RosahlHervé LucheRene de Waal MalefytFrontiers Media S.A.articleconditional KO miceIFN gammaPD-1mass cytometry (CyTOF)tumor immunity and immunotherapyCD8 T cellImmunologic diseases. AllergyRC581-607ENFrontiers in Immunology, Vol 12 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	conditional KO mice IFN gamma PD-1 mass cytometry (CyTOF) tumor immunity and immunotherapy CD8 T cell Immunologic diseases. Allergy RC581-607
spellingShingle	conditional KO mice IFN gamma PD-1 mass cytometry (CyTOF) tumor immunity and immunotherapy CD8 T cell Immunologic diseases. Allergy RC581-607 Sukanya Raghavan Sukanya Raghavan Nataliya Tovbis-Shifrin Christina Kochel Anandi Sawant Marielle Mello Manjiri Sathe Wendy Blumenschein Eric S. Muise Alissa Chackerian Elaine M. Pinheiro Thomas W. Rosahl Hervé Luche Rene de Waal Malefyt Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy
description	Programmed cell death-1 (PD-1) blockade has a profound effect on the ability of the immune system to eliminate tumors, but many questions remain about the cell types involved and the underlying mechanisms of immune activation. To shed some light on this, the cellular and molecular events following inhibition of PD-1 signaling was investigated in the MC-38 colon carcinoma model using constitutive (PD-1 KO) and conditional (PD1cKO) mice and in wild-type mice treated with PD-1 antibody. The impact on both tumor growth and the development of tumor immunity was assessed. In the PD-1cKO mice, a complete deletion of Pdcd1 in tumor-infiltrating T cells (TILs) after tamoxifen treatment led to the inhibition of tumor growth of both small and large tumors. Extensive immune phenotypic analysis of the TILs by flow and mass cytometry identified 20-different T cell subsets of which specifically 5-CD8 positive ones expanded in all three models after PD-1 blockade. All five subsets expressed granzyme B and interferon gamma (IFNγ). Gene expression analysis of the tumor further supported the phenotypic analysis in both PD-1cKO- and PD-1 Ab-treated mice and showed an upregulation of pathways related to CD4 and CD8 T-cell activation, enhanced signaling through costimulatory molecules and IFNγ, and non-T-cell processes. Altogether, using PD-1cKO mice, we define the intrinsic nature of PD-1 suppression of CD8 T-cell responses in tumor immunity.
format	article
author	Sukanya Raghavan Sukanya Raghavan Nataliya Tovbis-Shifrin Christina Kochel Anandi Sawant Marielle Mello Manjiri Sathe Wendy Blumenschein Eric S. Muise Alissa Chackerian Elaine M. Pinheiro Thomas W. Rosahl Hervé Luche Rene de Waal Malefyt
author_facet	Sukanya Raghavan Sukanya Raghavan Nataliya Tovbis-Shifrin Christina Kochel Anandi Sawant Marielle Mello Manjiri Sathe Wendy Blumenschein Eric S. Muise Alissa Chackerian Elaine M. Pinheiro Thomas W. Rosahl Hervé Luche Rene de Waal Malefyt
author_sort	Sukanya Raghavan
title	Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy
title_short	Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy
title_full	Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy
title_fullStr	Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy
title_full_unstemmed	Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy
title_sort	conditional deletion of pdcd1 identifies the cell-intrinsic action of pd-1 on functional cd8 t cell subsets for antitumor efficacy
publisher	Frontiers Media S.A.
publishDate	2021
url	https://doaj.org/article/72fd7ab5d05749e780b38e08a7d4a277
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Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy

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