Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China.
Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Quantitative Sciences Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
Cancer Cell. 2022 Nov 14;40(11):1374-1391.e7. doi: 10.1016/j.ccell.2022.10.001. Epub 2022 Oct 27.
Successful pancreatic ductal adenocarcinoma (PDAC) immunotherapy necessitates optimization and maintenance of activated effector T cells (Teff). We prospectively collected and applied multi-omic analyses to paired pre- and post-treatment PDAC specimens collected in a platform neoadjuvant study of granulocyte-macrophage colony-stimulating factor-secreting allogeneic PDAC vaccine (GVAX) vaccine ± nivolumab (anti-programmed cell death protein 1 [PD-1]) to uncover sensitivity and resistance mechanisms. We show that GVAX-induced tertiary lymphoid aggregates become immune-regulatory sites in response to GVAX + nivolumab. Higher densities of tumor-associated neutrophils (TANs) following GVAX + nivolumab portend poorer overall survival (OS). Increased T cells expressing CD137 associated with cytotoxic Teff signatures and correlated with increased OS. Bulk and single-cell RNA sequencing found that nivolumab alters CD4 T cell chemotaxis signaling in association with CD11b neutrophil degranulation, and CD8 T cell expression of CD137 was required for optimal T cell activation. These findings provide insights into PD-1-regulated immune pathways in PDAC that should inform more effective therapeutic combinations that include TAN regulators and T cell activators.
成功的胰腺导管腺癌 (PDAC) 免疫疗法需要优化和维持激活的效应 T 细胞 (Teff)。我们前瞻性地收集并应用多组学分析方法，对在粒细胞巨噬细胞集落刺激因子分泌同种异体 PDAC 疫苗 (GVAX) 疫苗 ± 纳武单抗 (抗程序性细胞死亡蛋白 1 [PD-1]) 的平台新辅助研究中收集的配对 PDAC 治疗前后标本进行分析，以揭示敏感性和耐药机制。我们表明，GVAX 诱导的三级淋巴样聚集在 GVAX + 纳武单抗作用下成为免疫调节部位。GVAX + 纳武单抗后肿瘤相关中性粒细胞 (TAN) 密度增加预示总体生存率 (OS) 较差。表达 CD137 的 T 细胞增加与细胞毒性 Teff 特征相关，并与 OS 增加相关。批量和单细胞 RNA 测序发现，纳武单抗改变 CD4 T 细胞趋化信号，与 CD11b 中性粒细胞脱颗粒相关，CD8 T 细胞表达 CD137 是 T 细胞最佳激活所必需的。这些发现为 PDAC 中 PD-1 调节的免疫途径提供了深入了解，这应该为包括 TAN 调节剂和 T 细胞激活剂在内的更有效的治疗组合提供信息。
