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

Autor:	Raghavan S; Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States.; Department of Microbiology and Immunology, Institute for Biomedicine, University of Gothenburg, Gothenburg, Sweden., Tovbis-Shifrin N; Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States., Kochel C; Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States., Sawant A; Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States., Mello M; Centre d'Immunophénomique - CIPHE (PHENOMIN), Aix Marseille Université (UMS3367), National Institute of Health and Medical Research (INSERM) (US012), The French National Centre for Scientific Research (CNRS) (UMS3367), Marseille, France., Sathe M; Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States., Blumenschein W; Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States., Muise ES; Merck & Co., Inc., Boston, MA, United States., Chackerian A; Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States., Pinheiro EM; Merck & Co., Inc., Boston, MA, United States., Rosahl TW; Merck & Co., Inc., Kenilworth, NJ, United States., Luche H; Centre d'Immunophénomique - CIPHE (PHENOMIN), Aix Marseille Université (UMS3367), National Institute of Health and Medical Research (INSERM) (US012), The French National Centre for Scientific Research (CNRS) (UMS3367), Marseille, France., de Waal Malefyt R; Department of Immunology, Merck & Co., Inc., Palo Alto, CA, United States.
Jazyk:	angličtina
Zdroj:	Frontiers in immunology [Front Immunol] 2021 Nov 29; Vol. 12, pp. 752348. Date of Electronic Publication: 2021 Nov 29 (Print Publication: 2021).
DOI:	10.3389/fimmu.2021.752348
Abstrakt:	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. Competing Interests: Authors SR, NT-S, AS, MS, EP and AC were employed by Merck & Co., Inc., Kenilworth, NJ, USA. CK and RW were employed by Merck & Co., Inc., Kenilworth, NJ, USA at the time of the study and are currently employed by Synthekine. WB, EM, and TR are currently employed by Merck & Co., Inc., Kenilworth, NJ, USA. (Copyright © 2021 Raghavan, Tovbis-Shifrin, Kochel, Sawant, Mello, Sathe, Blumenschein, Muise, Chackerian, Pinheiro, Rosahl, Luche and de Waal Malefyt.)
Databáze:	MEDLINE
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