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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...
Autores principales: | , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Frontiers Media S.A.
2021
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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. |
format | Online Article Text |
id | pubmed-8667167 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | Frontiers Media S.A. |
record_format | MEDLINE/PubMed |
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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