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

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. We investigated the functional role of cyclin-dependent kinase...

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Veröffentlicht in:Gastroenterology (New York, N.Y. 1943) N.Y. 1943), 2024-02, Vol.166 (2), p.284-297.e11
Hauptverfasser: Thoma, Oana-Maria, Naschberger, Elisabeth, Kubánková, Markéta, Larafa, Imen, Kramer, Viktoria, Menchicchi, Bianca, Merkel, Susanne, Britzen-Laurent, Nathalie, Jefremow, André, Grützmann, Robert, Koop, Kristina, Neufert, Clemens, Atreya, Raja, Guck, Jochen, Stürzl, Michael, Neurath, Markus F., Waldner, Maximilian J.
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container_end_page 297.e11
container_issue 2
container_start_page 284
container_title Gastroenterology (New York, N.Y. 1943)
container_volume 166
creator Thoma, Oana-Maria
Naschberger, Elisabeth
Kubánková, Markéta
Larafa, Imen
Kramer, Viktoria
Menchicchi, Bianca
Merkel, Susanne
Britzen-Laurent, Nathalie
Jefremow, André
Grützmann, Robert
Koop, Kristina
Neufert, Clemens
Atreya, Raja
Guck, Jochen
Stürzl, Michael
Neurath, Markus F.
Waldner, Maximilian J.
description 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. 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. 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. 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. [Display omitted] Gate-keeper p21 is important for preventing cluster of differentiation 4-positive T-cell exhaustion in colorectal cancer. Targeting the cell cycle machinery in cluster of differentiation 4-positive T cells might improve their antitumor response.
doi_str_mv 10.1053/j.gastro.2023.09.017
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T-cell reactivity to CRC is nevertheless limited by T-cell exhaustion. However, molecular mechanisms regulating T-cell exhaustion are only poorly understood. 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. 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. 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. [Display omitted] Gate-keeper p21 is important for preventing cluster of differentiation 4-positive T-cell exhaustion in colorectal cancer. 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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. 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. [Display omitted] Gate-keeper p21 is important for preventing cluster of differentiation 4-positive T-cell exhaustion in colorectal cancer. 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subjects Animals
CD4+ T Cells
Colorectal Cancer
Colorectal Neoplasms - pathology
Cyclin-Dependent Kinase Inhibitor p21 - metabolism
Cyclin-Dependent Kinases - metabolism
Humans
Immunity
Mice
p21
Palbociclib
Th1 Cells
title p21 Prevents the Exhaustion of CD4+ T Cells Within the Antitumor Immune Response Against Colorectal Cancer
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