Montagne Janelle M, Mitchell Jacob T, Tandurella Joseph A, Christenson Eric S, Danilova Ludmila V, Deshpande Atul, Loth Melanie, Sidiropoulos Dimitrios N, Davis-Marcisak Emily, Bergman Daniel R, Zhu Qingfeng, Wang Hao, Kagohara Luciane T, Engle Logan L, Green Benjamin F, Favorov Alexander V, Ho Won Jin, Lim Su Jin, Zhang Rui, Li Pan, Gai Jessica, Mo Guanglan, Mitchell Sarah, Wang Rulin, Vaghasia Ajay, Hou Wenpin, Xu Yao, Zimmerman Jacquelyn W, Elisseeff Jennifer H, Yegnasubramanian Srinivasan, Anders Robert A, Jaffee Elizabeth M, Zheng Lei, Fertig Elana J
Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
Convergence Institute, Johns Hopkins University School of Medicine, Baltimore, MD, USA.
iScience. 2024 Dec 10;28(1):111569. doi: 10.1016/j.isci.2024.111569. eCollection 2025 Jan 17.
Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy requires therapeutic combinations that induce quality T cells. Tumor microenvironment (TME) analysis following therapeutic interventions can identify response mechanisms, informing design of effective combinations. We provide a reference single-cell dataset from tumor-infiltrating leukocytes (TILs) from a human neoadjuvant clinical trial comparing the granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting allogeneic PDAC vaccine GVAX alone, in combination with anti-PD1 or with both anti-PD1 and CD137 agonist. Treatment with GVAX and anti-PD-1 led to increased CD8 T cell activation and expression of cytoskeletal and extracellular matrix (ECM)-interacting components. Addition of CD137 agonist increased abundance of clonally expanded CD8 T cells and increased immunosuppressive TREM2 signaling in tumor associated macrophages (TAMs), identified by comparison of ligand-receptor networks, corresponding to changes in metabolism and ECM interactions. These findings associate therapy with GVAX, anti-PD1, and CD137 agonist with enhanced CD8 T cell function while inducing alternative immunosuppressive pathways in patients with PDAC.
成功的胰腺导管腺癌（PDAC）免疫疗法需要能诱导高质量T细胞的治疗组合。治疗干预后的肿瘤微环境（TME）分析可以识别反应机制，为有效组合的设计提供依据。我们提供了一个来自人类新辅助临床试验的肿瘤浸润白细胞（TILs）的参考单细胞数据集，该试验比较了单独使用分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF）的同种异体PDAC疫苗GVAX、与抗PD1联合使用或与抗PD1和CD137激动剂两者联合使用的情况。用GVAX和抗PD-1治疗导致CD8 T细胞活化增加以及细胞骨架和细胞外基质（ECM）相互作用成分的表达增加。通过配体-受体网络比较确定，添加CD137激动剂增加了克隆扩增的CD8 T细胞的丰度，并增加了肿瘤相关巨噬细胞（TAM）中免疫抑制性TREM2信号传导，这与代谢和ECM相互作用的变化相对应。这些发现将GVAX、抗PD1和CD137激动剂的治疗与增强的CD8 T细胞功能联系起来，同时在PDAC患者中诱导了替代性免疫抑制途径。
