p21 Prevents the Exhaustion of CD4 + T Cells Within the Antitumor Immune Response Against Colorectal Cancer.

Autor:	Thoma OM; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany. Electronic address: oana-maria.thoma@uk-erlangen.de., Naschberger E; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Division of Molecular and Experimental Surgery, Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Kubánková M; Max Planck Institute for the Science of Light & Max-Planck-Zentrum für Physik und Medizin, Erlangen, Germany., Larafa I; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Kramer V; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Menchicchi B; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Merkel S; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Britzen-Laurent N; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Jefremow A; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Grützmann R; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Koop K; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Neufert C; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Atreya R; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Guck J; Max Planck Institute for the Science of Light & Max-Planck-Zentrum für Physik und Medizin, Erlangen, Germany., Stürzl M; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Division of Molecular and Experimental Surgery, Department of Surgery, University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany., Neurath MF; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany., Waldner MJ; Department of Medicine 1, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; German Center for Immunotherapy, Deutsches Zentrum Immuntherapie (DZI), University Hospital Erlangen, Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany; Comprehensive Cancer Center Erlangen-EMN (CCC ER-EMN), Erlangen, Germany; Erlangen Graduate School in Advanced Optical Technologies (SAOT), Friedrich-Alexander-Universität Erlangen-Nürnberg, Erlangen, Germany.
Jazyk:	angličtina
Zdroj:	Gastroenterology [Gastroenterology] 2024 Feb; Vol. 166 (2), pp. 284-297.e11. Date of Electronic Publication: 2023 Sep 19.
DOI:	10.1053/j.gastro.2023.09.017
Abstrakt:	Background & Aims: T cells are crucial for the antitumor response against colorectal cancer (CRC). T-cell reactivity to CRC is nevertheless limited by T-cell exhaustion. However, molecular mechanisms regulating T-cell exhaustion are only poorly understood. Methods: We investigated the functional role of cyclin-dependent kinase 1a (Cdkn1a or p21) in cluster of differentiation (CD) 4 + T cells using murine CRC models. Furthermore, we evaluated the expression of p21 in patients with stage I to IV CRC. In vitro coculture models were used to understand the effector function of p21-deficient CD4 + T cells. Results: We observed that the activation of cell cycle regulator p21 is crucial for CD4 + T-cell cytotoxic function and that p21 deficiency in type 1 helper T cells (Th1) leads to increased tumor growth in murine CRC. Similarly, low p21 expression in CD4 + T cells infiltrated into tumors of CRC patients is associated with reduced cancer-related survival. In mouse models of CRC, p21-deficient Th1 cells show signs of exhaustion, where an accumulation of effector/effector memory T cells and CD27/CD28 loss are predominant. Immune reconstitution of tumor-bearing Rag1 -/- mice using ex vivo-treated p21-deficient T cells with palbociclib, an inhibitor of cyclin-dependent kinase 4/6, restored cytotoxic function and prevented exhaustion of p21-deficient CD4 + T cells as a possible concept for future immunotherapy of human disease. Conclusions: Our data reveal the importance of p21 in controlling the cell cycle and preventing exhaustion of Th1 cells. Furthermore, we unveil the therapeutic potential of cyclin-dependent kinase inhibitors such as palbociclib to reduce T-cell exhaustion for future treatment of patients with colorectal cancer. (Copyright © 2024 The Authors. Published by Elsevier Inc. All rights reserved.)
Databáze:	MEDLINE
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