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

Keyu Li; Joseph A Tandurella; Jessica Gai; Qingfeng Zhu; Su Jin Lim; Dwayne L Thomas 2nd; Tao Xia; Guanglan Mo; Jacob T Mitchell; Janelle Montagne; Melissa Lyman; Ludmila V Danilova; Jacquelyn W Zimmerman; Benedict Kinny-Köster; 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; Elizabeth D Thompson; Hao Wang; Elana J Fertig; Elizabeth M Jaffee; Lei Zheng

doi:10.1016/j.ccell.2022.10.001

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

Cancer Cell. 2022 Nov 14;40(11):1374-1391.e7. doi: 10.1016/j.ccell.2022.10.001. Epub 2022 Oct 27.

Authors

Keyu Li¹, Joseph A Tandurella², Jessica Gai³, Qingfeng Zhu⁴, Su Jin Lim⁵, Dwayne L Thomas 2nd⁶, Tao Xia⁷, Guanglan Mo³, Jacob T Mitchell⁸, Janelle Montagne², Melissa Lyman⁹, Ludmila V Danilova², Jacquelyn W Zimmerman², Benedict Kinny-Köster¹⁰, Tengyi Zhang⁷, Linda Chen¹¹, Alex B Blair¹², Thatcher Heumann¹³, Rose Parkinson¹⁴, Jennifer N Durham¹⁴, Amol K Narang¹⁵, Robert A Anders¹⁶, Christopher L Wolfgang¹⁷, Daniel A Laheru¹², Jin He¹⁷, Arsen Osipov³, Elizabeth D Thompson¹⁸, Hao Wang¹⁹, Elana J Fertig²⁰, Elizabeth M Jaffee²¹, Lei Zheng²²

Affiliations

¹ 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.
² 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.
³ 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 Skip Viragh Pancreatic 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.
⁴ 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 Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁵ 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; 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.
⁶ 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 Skip Viragh Pancreatic 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 Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
⁷ 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.
⁸ 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; Department of Genetic Medicine, Johns Hopkins University School of Medicine, Baltimore, MD 21205, USA.
⁹ 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 Skip Viragh Pancreatic 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.
¹⁰ 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 Skip Viragh Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹¹ 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; Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹² 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 Skip Viragh Pancreatic 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; The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹³ 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.
¹⁴ 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 Skip Viragh Pancreatic 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; The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁵ 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 Skip Viragh Pancreatic 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; Department of Radiation Oncology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁶ 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 Skip Viragh Pancreatic 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; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁷ 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 Skip Viragh Pancreatic 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; Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁸ 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 Skip Viragh Pancreatic 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; Department of Pathology, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA.
¹⁹ 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; 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.
²⁰ 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; Department of Applied Mathematics and Statistics, Johns Hopkins University Whiting School of Engineering, Baltimore, MD 21218, USA; Department of Biomedical Engineering, Johns Hopkins University School of Medicine, Baltimore, MD 21218, USA. Electronic address: ejfertig@jhmi.edu.
²¹ 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 Skip Viragh Pancreatic 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; The Cancer Convergence Institute at Johns Hopkins, Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA. Electronic address: ejaffee@jhmi.edu.
²² 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 Skip Viragh Pancreatic 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 Surgery, 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. Electronic address: lzheng6@jhmi.edu.

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.

Keywords: CD137; IL-8; RNA sequencing; Th17; anti-PD-1 antibody; immune checkpoint inhibitor; multiplex immunohistochemistry; pancreatic cancer; tumor-associated neutrophils; vaccine therapy.

Publication types

Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural

MeSH terms

Adenocarcinoma* / drug therapy
Adenocarcinoma* / genetics
Carcinoma, Pancreatic Ductal* / drug therapy
Carcinoma, Pancreatic Ductal* / genetics
Humans
Neoadjuvant Therapy
Nivolumab / pharmacology
Nivolumab / therapeutic use
Pancreatic Neoplasms* / drug therapy
Pancreatic Neoplasms* / genetics
Tumor Microenvironment

Substances

Nivolumab

Abstract

Publication types

MeSH terms

Substances

Grants and funding