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Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy

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Pubmed体系：

收录情况： ◇ 自然指数

作者：
Keyu Li[1,2,4,5,12] ; Joseph A. Tandurella[1,2,5,6,10] ; Jessica Gai[1,2,3,4,5] ; Qingfeng Zhu[1,2,4,5,7] ; Su Jin Lim[1,2,6,10] ; Dwayne L. Thomas[1,2,3,4,5,8] ; Tao Xia[1,2,4,5] ; Guanglan Mo[1,2,3,4,5] ; Jacob T. Mitchell[1,2,5,6,10,11] ; Janelle Montagne[1,2,5,6,10] ; Melissa Lyman[2,3,5,6,10] ; Ludmila V. Danilova[2,5,6,10] ; Jacquelyn W. Zimmerman[1,2,5,6,10] ; Benedict Kinny-Koster[1,2,3,8] ; Tengyi Zhang[1,2,4,5] ; Linda Chen[1,2,9] ; Alex B. Blair[1,2,3,4,5,10] ; Thatcher Heumann[1,2] ; Rose Parkinson[1,2,3,5,10] ; Jennifer N. Durham[1,2,3,5,10] ; Amol K. Narang[1,2,3,4,9] ; Robert A. Anders[1,2,3,5,7] ; Christopher L. Wolfgang[1,2,3,4,8] ; Daniel A. L aheru[1,2,3,4,5,10] ; Jin He[1,2,3,4,8] ; Arsen Osipov[1,2,3,4,5] ; Elizabeth D. Thompson[1,2,3,4,7] ; Hao Wang[1,2,4,5,6,10] ; Elana J. Fertig[1,2,5,6,10,13,14] ; Elizabeth M. Jaffee[1,2,3,4,5,10] ; Lei Zheng[1,2,3,4,5,8,10] ;
机构： [1]Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [2]The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [3]The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [4]The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [5]The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [6]Quantitative Sciences Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [7]Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [8]Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [9]Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [10]The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [11]Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA [12]Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China [13]Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA [14]Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA
出处：
DOI： 10.1016/j.ccell.2022.10.001
ISSN：

摘要：
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.Copyright © 2022 The Author(s). Published by Elsevier Inc. All rights reserved.

基金：
This study was supported by NIH grants R01 CA169702 (L.Z.), R01 CA197296 (L.Z., E.M.J.), P50 CA062924 (E.M.J., L.Z.), a Bristol-Myers Squibb grant (E.M.J., L.Z.), Viragh Foundation and Skip Viragh Pancreatic Cancer Center at Johns Hopkins (E.M.J., L.Z.), and NCI P30 CA006973. RNA-seq was sup￾ported by a grant from iTeos (L.Z.), which is independent from the collaboration with Bristol-Myers Squibb. DNA sequencing and analysis was supported by a collaborative project at Johns Hopkins University inHealth Program and Preci￾sion Medicine Application Platform. We thank Drs. Dongbing Liu, Fanfan Xie, and Mengyue Lei at BGI Genomics, Inc. for their technical advice. B.K. is sup￾ported by the German Research Foundation (KI 2437/2-1).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类 | 1 区 医学
小类 | 1 区 肿瘤学 1 区 细胞生物学
最新[2023]版：
大类 | 1 区 医学
小类 | 1 区 细胞生物学 1 区 肿瘤学
第一作者：
第一作者机构： [1]Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [2]The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [4]The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [5]The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [12]Department of Pancreatic Surgery, West China Hospital, Sichuan University, Chengdu, Sichuan 610041, China
共同第一作者：
通讯作者：
通讯机构： [1]Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [2]The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [3]The Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [4]The Pancreatic Cancer Precision Medicine Center of Excellence Program, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [5]The Bloomberg Kimmel Institute for Cancer Immunotherapy, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [6]Quantitative Sciences Division, Department of Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [8]Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [10]The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA [13]Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA [14]Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA
推荐引用方式(GB/T 7714)：
Keyu Li,Joseph A. Tandurella,Jessica Gai,et al.Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy[J].Cancer cell.2022,doi:10.1016/j.ccell.2022.10.001.
APA：
Keyu Li,Joseph A. Tandurella,Jessica Gai,Qingfeng Zhu,Su Jin Lim...&Lei Zheng.(2022).Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy.Cancer cell,,
MLA：
Keyu Li,et al."Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy".Cancer cell .(2022)

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