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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

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: Raghavan, Sukanya, Tovbis-Shifrin, Nataliya, Kochel, Christina, Sawant, Anandi, Mello, Marielle, Sathe, Manjiri, Blumenschein, Wendy, Muise, Eric S., Chackerian, Alissa, Pinheiro, Elaine M., Rosahl, Thomas W., Luche, Hervé, de Waal Malefyt, Rene
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667167/
https://www.ncbi.nlm.nih.gov/pubmed/34912335
http://dx.doi.org/10.3389/fimmu.2021.752348
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author Raghavan, Sukanya
Tovbis-Shifrin, Nataliya
Kochel, Christina
Sawant, Anandi
Mello, Marielle
Sathe, Manjiri
Blumenschein, Wendy
Muise, Eric S.
Chackerian, Alissa
Pinheiro, Elaine M.
Rosahl, Thomas W.
Luche, Hervé
de Waal Malefyt, Rene
author_facet Raghavan, Sukanya
Tovbis-Shifrin, Nataliya
Kochel, Christina
Sawant, Anandi
Mello, Marielle
Sathe, Manjiri
Blumenschein, Wendy
Muise, Eric S.
Chackerian, Alissa
Pinheiro, Elaine M.
Rosahl, Thomas W.
Luche, Hervé
de Waal Malefyt, Rene
author_sort Raghavan, Sukanya
collection PubMed
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.
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spelling pubmed-86671672021-12-14 Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy Raghavan, Sukanya Tovbis-Shifrin, Nataliya Kochel, Christina Sawant, Anandi Mello, Marielle Sathe, Manjiri Blumenschein, Wendy Muise, Eric S. Chackerian, Alissa Pinheiro, Elaine M. Rosahl, Thomas W. Luche, Hervé de Waal Malefyt, Rene Front Immunol Immunology 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. Frontiers Media S.A. 2021-11-29 /pmc/articles/PMC8667167/ /pubmed/34912335 http://dx.doi.org/10.3389/fimmu.2021.752348 Text en Copyright © 2021 Raghavan, Tovbis-Shifrin, Kochel, Sawant, Mello, Sathe, Blumenschein, Muise, Chackerian, Pinheiro, Rosahl, Luche and de Waal Malefyt https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Immunology
Raghavan, Sukanya
Tovbis-Shifrin, Nataliya
Kochel, Christina
Sawant, Anandi
Mello, Marielle
Sathe, Manjiri
Blumenschein, Wendy
Muise, Eric S.
Chackerian, Alissa
Pinheiro, Elaine M.
Rosahl, Thomas W.
Luche, Hervé
de Waal Malefyt, Rene
Conditional Deletion of Pdcd1 Identifies the Cell-Intrinsic Action of PD-1 on Functional CD8 T Cell Subsets for Antitumor Efficacy
title 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_short 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
topic Immunology
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8667167/
https://www.ncbi.nlm.nih.gov/pubmed/34912335
http://dx.doi.org/10.3389/fimmu.2021.752348
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