Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy.
Multi-omic analyses of changes in the tumor microenvironment of pancreatic adenocarcinoma following neoadjuvant treatment with anti-PD-1 therapy.
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DOI：
10.1016/j.ccell.2022.10.001
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发表时间：
2022-11-14
期刊：
影响因子：
50.3
通讯作者：
Zheng, Lei
中科院分区：
文献类型：
--
作者：
Li, Keyu;Tandurella, Joseph A.;Gai, Jessica;Zhu, Qingfeng;Lim, Su Jin;Thomas II, Dwayne L.;Xia, Tao;Mo, Guanglan;Mitchell, Jacob T.;Montagne, Janelle;Lyman, Melissa;Danilova, Ludmila, V;Zimmerman, Jacquelyn W.;Kinny-Koster, Benedict;Zhang, Tengyi;Chen, Linda;Blair, Alex B.;Heumann, Thatcher;Parkinson, Rose;Durham, Jennifer N.;Narang, Amol K.;Anders, Robert A.;Wolfgang, Christopher L.;Laheru, Daniel A.;He, Jin;Osipov, Arsen;Thompson, Elizabeth D.;Wang, Hao;Fertig, Elana J.;Jaffee, Elizabeth M.;Zheng, Lei
成功的胰腺导管腺癌（PDAC）免疫疗法需要活化的效应T细胞（Teff）的优化和维持。我们前瞻性地收集了治疗前和治疗后配对的PDAC标本，并将多组学分析应用于粒细胞-巨噬细胞集落刺激因子分泌的同种异体PDAC疫苗（GVAX）疫苗± nivolumab（抗程序性细胞死亡蛋白1 [PD-1]）的平台新辅助研究中，以揭示敏感性和耐药机制。我们表明，GVAX诱导的三级淋巴聚集体成为响应GVAX + nivolumab的免疫调节位点。GVAX +纳武单抗后肿瘤相关中性粒细胞（TAN）密度较高预示着总体生存期（OS）较差。大量和单细胞RNA测序发现，纳武单抗改变与CD 11b+中性粒细胞脱粒相关的CD 4 + T细胞趋化性信号传导，并且CD 137的CD 8 + T细胞表达是最佳T细胞活化所需的。这些发现为PDAC中PD-1调节的免疫途径提供了见解，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。Li等人对来自胰腺癌新辅助平台试验的治疗前和治疗后标本进行了多组学分析，并确定了与抗PD-1联合治疗相关的敏感性和耐药机制。结果表明，肿瘤相关中性粒细胞预后较差，但CD 137 + CD 8 + T细胞预后较好，为未来的干预措施提出了治疗策略。
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. Li et al. perform multi-omic analyses on pre- and post-treatment specimens from a pancreatic cancer neoadjuvant platform trial, and identify sensitivity and resistance mechanisms associated with anti-PD-1 combination therapy. Results associate tumor-associated neutrophils with poor outcomes but CD137+CD8+ T cells with better outcomes, suggesting treatment strategies for future interventions.
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