CELL INTELLIGENCE · 肿瘤细胞治疗研究
肿瘤细胞治疗研究
英文原题：CD137 agonism enhances anti-PD1 induced activation of expanded CD8(+) T cell clones in a neoadjuvant pancreatic cancer clinical trial.
CD137 agonism enhances anti-PD1 induced activation of expanded CD8(+) T cell clones in a neoadjuvant pancreatic cancer clinical trial.
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成功的胰腺导管腺癌（PDAC）免疫治疗需要能够诱导高质量T细胞的治疗性联合方案。治疗干预后的肿瘤微环境（TME）分析可以识别应答机制，为设计有效联合方案提供依据。
我们提供了一份来自人类新辅助临床试验中肿瘤浸润白细胞（TILs）的参考单细胞数据集，该试验比较了分泌粒细胞-巨噬细胞集落刺激因子（GM-CSF）的同种异体PDAC疫苗GVAX单用、联合抗PD1、或联合抗PD1和CD137激动剂的方案。GVAX联合抗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）相互作用组分的表达增加。加入CD137激动剂后，克隆扩增的CD8+ T细胞丰度增加，并且通过配体-受体网络比较发现，肿瘤相关巨噬细胞（TAMs）中免疫抑制性TREM2信号增强，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PDAC患者中CD8+ T细胞功能增强以及替代性免疫抑制通路的诱导联系起来。
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.
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