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

Thoma OM, Naschberger E, Kubánková M, Larafa I, Kramer V, Menchicchi B, Merkel S, Britzen-Laurent N, Jefremow A, Grützmann R, Koop K, Neufert C, Atreya R, Guck J, Stürzl M, Neurath M, Waldner M (2024)

Publication Type: Journal article

Publication year: 2024

Journal

Gastroenterology Elsevier

Book Volume: 166

Pages Range: 284-297.e11

Journal Issue: 2

DOI: 10.1053/j.gastro.2023.09.017

Abstract

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.

Authors with CRIS profile

Oana-Maria Thoma Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Elisabeth Naschberger Department of Surgery Imen Larafa Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Susanne Merkel Department of Surgery Nathalie Britzen-Laurent Medizinische Fakultät Robert Grützmann Lehrstuhl für Allgemein- und Viszeralchirurgie Kristina Koop Department of Medicine 1 – Gastroenterology, Pneumology and Endocrinology Clemens Neufert Medizinische Fakultät Raja Atreya Professur für Translationale Immunforschung bei chronisch entzündlichen Darmerkrankungen (Heisenberg-Professur) Jochen Guck
Michael Stürzl Professur für Molekulare und Experimentelle Chirurgie Markus Neurath Lehrstuhl für Innere Medizin I Maximilian Waldner Professur für Funktionelle Bildgebung in der Medizin

Additional Organisation(s)

Interdisziplinäres Zentrum für Klinische Forschung

Related research project(s)

A097: Mucosal healing in IBD: deciphering the role of STAT3 activation in intestinal mesenchymal cell populations July 1, 2023 - Dec. 31, 2025

Involved external institutions

Max-Planck-Institut für die Physik des Lichts (MPL) / Max Planck Institute for the Science of Light DE Germany (DE)

How to cite

APA:

Thoma, O.-M., Naschberger, E., Kubánková, M., Larafa, I., Kramer, V., Menchicchi, B.,... Waldner, M. (2024). p21 Prevents the Exhaustion of CD4+ T Cells Within the Antitumor Immune Response Against Colorectal Cancer. Gastroenterology, 166(2), 284-297.e11. https://doi.org/10.1053/j.gastro.2023.09.017

MLA:

Thoma, Oana-Maria, et al. "p21 Prevents the Exhaustion of CD4+ T Cells Within the Antitumor Immune Response Against Colorectal Cancer." Gastroenterology 166.2 (2024): 284-297.e11.

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