小柯机器人

科学家完成抗PD-1疗法新辅助治疗后胰腺癌肿瘤微环境变化的多组学分析
2022-10-30 20:14
来源：小柯机器人

美国约翰霍普金斯大学医学院Arsen Osipov等研究人员合作完成抗PD-1疗法新辅助治疗后胰腺癌肿瘤微环境变化的多组学分析。这一研究成果于2022年10月27日在线发表在国际学术期刊《癌细胞》上。

成功的胰腺导管腺癌（PDAC）免疫治疗需要优化和维持活化的效应T细胞（Teff）。研究人员前瞻性地收集并应用多组学分析，对颗粒细胞-巨噬细胞集落刺激因子分泌的异体PDAC疫苗（GVAX）疫苗±nivolumab（抗程序化细胞死亡蛋白1[PD-1]）的平台新辅助研究中，收集的配对的治疗前和治疗后PDAC标本进行了分析，从而揭示了敏感性和抗性机制。结果表明，在对GVAX+nivolumab的反应中，GVAX诱导的三级淋巴细胞聚集成为免疫调节部位。GVAX+nivolumab后，肿瘤相关中性粒细胞（TAN）的密度较高，预示着总生存率（OS）较差。表达CD137的T细胞增加与细胞毒性Teff特征有关，并与OS增加相关。
 
大量和单细胞RNA测序发现，nivolumab改变了与CD11b+中性粒细胞脱颗粒有关的CD4+T细胞趋化信号，而CD8+T细胞表达CD137是最佳T细胞激活的必要条件。这些发现为PD-1调节PDAC的免疫途径提供了见解，有望为包括TAN调节剂和T细胞激活剂的更有效治疗组合提供信息。
 
附：英文原文

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

Author: Keyu Li, Joseph A. Tandurella, Jessica Gai, Qingfeng Zhu, Su Jin Lim, Dwayne L. Thomas, Tao Xia, Guanglan Mo, Jacob T. Mitchell, Janelle Montagne, Melissa Lyman, Ludmila V. Danilova, Jacquelyn W. Zimmerman, Benedict Kinny-Kster, Tengyi Zhang, Linda Chen, Alex B. Blair, Thatcher Heumann, Rose Parkinson, Jennifer N. Durham, Amol K. Narang, Robert A. Anders, Christopher L. Wolfgang, Daniel A. Laheru, Jin He, Arsen Osipov

Issue&Volume: 2022-10-27

Abstract: 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.

DOI: 10.1016/j.ccell.2022.10.001

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(22)00492-5

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
官方网址：https://www.cell.com/cancer-cell/home
投稿链接：https://www.editorialmanager.com/cancer-cell/default.aspx


本期文章：《癌细胞》：Online/在线发表

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