p21阻止了CD4+ T细胞在抗结直肠癌免疫应答中的衰竭。
p21 prevents the exhaustion of CD4+ T cells within the antitumor immune response against colorectal cancer.
发表日期：2023 Sep 19
作者：
Oana-Maria Thoma, Elisabeth Naschberger, Markéta Kubánková, Imen Larafa, Viktoria Kramer, Bianca Menchicchi, Susanne Merkel, Nathalie Britzen-Laurent, André Jefremow, Robert Grützmann, Kristina Koop, Clemens Neufert, Raja Atreya, Jochen Guck, Michael Stürzl, Markus F Neurath, Maximilian J Waldner
来源：
Disease Models & Mechanisms
摘要：
T细胞对于抗击结直肠癌（CRC）的肿瘤反应至关重要。然而，T细胞对CRC的反应受到了T细胞疲劳的限制。然而，调节T细胞疲劳的分子机制尚不清楚。我们使用小鼠CRC模型研究了细胞周期调控因子Cdkn1a或p21在CD4+ T细胞中的功能作用。此外，我们评估了p21在I-IV期CRC患者中的表达情况。我们使用体外共培养模型来了解p21缺陷CD4+ T细胞的效应功能。我们观察到，细胞周期调控因子p21的激活对于CD4+ T细胞的细胞毒作用至关重要，而Th1细胞中的p21缺陷导致小鼠CRC的肿瘤生长增加。同样，CD4+ T细胞在CRC患者肿瘤浸润中的低p21表达与癌症相关生存减少有关。在小鼠CRC模型中，p21缺陷的Th1细胞显示出疲劳的迹象，其中效应者/效应记忆T细胞和CD27/CD28丧失占主导地位。通过使用CDK4/6抑制剂Palbociclib体外处理的p21缺陷T细胞重新重建肿瘤患者Rag1-/-小鼠的免疫，恢复了细胞毒作用并预防了p21缺陷CD4+ T细胞的疲劳，为未来人类疾病的免疫治疗提供了可能的概念。我们的数据揭示了p21在调控细胞周期和预防Th1细胞疲劳中的重要性。此外，我们揭示了CDK抑制剂如Palbociclib减少T细胞疲劳在未来治疗结直肠癌患者中的治疗潜力。版权所有©2023 AGA Institute.由Elsevier Inc.出版。版权所有。
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 CD4+ T cells using murine CRC models. Furthermore, we evaluated the expression of p21 in patients with stage I-IV CRC. In vitro co-culture 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 Th1 cells 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 CDK4/6, 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 cell cycle and preventing exhaustion of Th1 cells. Furthermore, we unveil the therapeutic potential of CDK inhibitors such as Palbociclib to reduce T cell exhaustion for future treatment of patients with colorectal cancer.Copyright © 2023 AGA Institute. Published by Elsevier Inc. All rights reserved.