Kurzay Annina, Fresnillo Saló Sara, Rahbech Anne, Seremet Tina, Oelvang Madsen Cecilie, Chamberlain Christopher Aled, Bülow Jensen Emilie, Thy Luu Viet, Met Özcan, Peeters Marlies J W, Straten Per Thor
National Center for Cancer Immune Therapy, Department of Oncology, University Hospital Herlev, Herlev, Denmark.
Experimental and Translational Immunology, Department of Health Technology, Technical University of Denmark, Kongens Lyngby, Denmark.
Oncoimmunology. 2025 Dec;14(1):2532662. doi: 10.1080/2162402X.2025.2532662. Epub 2025 Jul 13.
Cancer immunotherapy predominantly targets CD8 T cells, but recent evidence highlights the importance of CD4 T cells in adoptive cell therapy (ACT). The TAM receptor MerTK regulates immune responses and has been shown to provide costimulatory signals in CD8 T cells. However, its role in CD4 T cells remains poorly understood. Here, we demonstrate that ProS1-MerTK signaling is upregulated in activated CD4 T cells, where it enhances central memory formation, metabolic fitness, and proliferation. Mechanistically, ProS1-MerTK signaling was linked to type 1 immune responses, suggesting a regulatory role in CD4 T cell polarization. Using CRISPR-Cas9-mediated knockout, we found that loss of MerTK reduced CD4 T cell fitness, function, and polarization. Furthermore, when ProS1 was added during the expansion of tumor-infiltrating lymphocytes (TILs) from advanced melanoma biopsies, it showed potential to promote favorable CD4 T cell memory and helper phenotypes, increase stemness, and reduce exhaustion - features associated with improved responses to ACT. These findings establish ProS1-MerTK as a key pathway for modulating CD4 T cell functionality and highlight its therapeutic potential to enhance TIL-based ACT outcomes.
癌症免疫疗法主要针对CD8 T细胞，但最近的证据凸显了CD4 T细胞在过继性细胞疗法（ACT）中的重要性。TAM受体MerTK调节免疫反应，并且已被证明能在CD8 T细胞中提供共刺激信号。然而，其在CD4 T细胞中的作用仍知之甚少。在此，我们证明ProS1-MerTK信号在活化的CD4 T细胞中上调，在其中它增强了中央记忆形成、代谢适应性和增殖。从机制上讲，ProS1-MerTK信号与1型免疫反应相关，提示其在CD4 T细胞极化中起调节作用。使用CRISPR-Cas9介导的基因敲除，我们发现MerTK的缺失降低了CD4 T细胞的适应性、功能和极化。此外，当在从晚期黑色素瘤活检组织中扩增肿瘤浸润淋巴细胞（TILs）时添加ProS1，它显示出促进有利的CD4 T细胞记忆和辅助表型、增加干性并减少耗竭的潜力——这些特征与对ACT的反应改善相关。这些发现确立了ProS1-MerTK作为调节CD4 T细胞功能的关键途径，并突出了其增强基于TIL的ACT疗效的治疗潜力。
