title: Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is considered a "nonimmunogenic" neoplasm. Single-agent immunotherapies have failed to demonstrate significant clinical activity in PDAC and other "nonimmunogenic" tumors, in part due to a complex tumor microenvironment (TME) that provides a formidable barrier to immune infiltration and function. We designed a neoadjuvant and adjuvant clinical trial comparing an irradiated, granulocyte-macrophage colony-stimulating factor (GM-CSF)-secreting, allogeneic PDAC vaccine (GVAX) given as a single agent or in combination with low-dose cyclophosphamide to deplete regulatory T cells (Treg) as a means to study how the TME is altered by immunotherapy. Examination of resected PDACs revealed the formation of vaccine-induced intratumoral tertiary lymphoid aggregates in 33 of 39 patients 2 weeks after vaccine treatment. Immunohistochemical analysis showed these aggregates to be regulatory structures of adaptive immunity. Microarray analysis of microdissected aggregates identified gene-expression signatures in five signaling pathways involved in regulating immune-cell activation and trafficking that were associated with improved postvaccination responses. A suppressed Treg pathway and an enhanced Th17 pathway within these aggregates were associated with improved survival, enhanced postvaccination mesothelin-specific T-cell responses, and increased intratumoral Teff:Treg ratios. This study provides the first example of immune-based therapy converting a "nonimmunogenic" neoplasm into an "immunogenic" neoplasm by inducing infiltration of T cells and development of tertiary lymphoid structures in the TME. Post-GVAX T-cell infiltration and aggregate formation resulted in the upregulation of immunosuppressive regulatory mechanisms, including the PD-1-PD-L1 pathway, suggesting that patients with vaccine-primed PDAC may be better candidates than vaccine-naïve patients for immune checkpoint and other immunomodulatory therapies.
authors.affiliation: Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Eric R
authors.initials: ER
authors.lastname: Lutz
authors.affiliation: Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center;
authors.forename: Annie A
authors.initials: AA
authors.lastname: Wu
authors.affiliation: Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center;
authors.forename: Elaine
authors.initials: E
authors.lastname: Bigelow
authors.affiliation: Pathology, and.
authors.forename: Rajni
authors.initials: R
authors.lastname: Sharma
authors.affiliation: Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care;
authors.forename: Guanglan
authors.initials: G
authors.lastname: Mo
authors.affiliation: Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Kevin
authors.initials: K
authors.lastname: Soares
authors.affiliation: Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care;
authors.forename: Sara
authors.initials: S
authors.lastname: Solt
authors.affiliation: Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care;
authors.forename: Alvin
authors.initials: A
authors.lastname: Dorman
authors.affiliation: Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care;
authors.forename: Anthony
authors.initials: A
authors.lastname: Wamwea
authors.affiliation: Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center;
authors.forename: Allison
authors.initials: A
authors.lastname: Yager
authors.affiliation: Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care;
authors.forename: Daniel
authors.initials: D
authors.lastname: Laheru
authors.affiliation: Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Wolfgang
authors.affiliation: Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
authors.forename: Jiang
authors.initials: J
authors.lastname: Wang
authors.affiliation: Authors' Affiliations: Departments of Oncology, Pathology, and The Sidney Kimmel Cancer Center; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: Authors' Affiliations: Departments of Oncology, Pathology, and The Sidney Kimmel Cancer Center; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and.
authors.forename: Robert A
authors.initials: RA
authors.lastname: Anders
authors.affiliation: Authors' Affiliations: Departments of Oncology, Pathology, and The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and lzheng6@jhmi.edu ejaffee@jhmi.edu.
authors.forename: Elizabeth M
authors.initials: EM
authors.lastname: Jaffee
authors.affiliation: Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care; The Sol Goldman Pancreatic Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland; and lzheng6@jhmi.edu ejaffee@jhmi.edu.
authors.forename: Lei
authors.initials: L
authors.lastname: Zheng
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D018906:Antineoplastic Agents, Alkylating / Q000008:administration & dosage / Q000627:therapeutic use; D019496:Cancer Vaccines / Q000627:therapeutic use*; D002449:Cell Aggregation / Q000276:immunology; D017024:Chemotherapy, Adjuvant; D003520:Cyclophosphamide / Q000008:administration & dosage / Q000627:therapeutic use; D004334:Drug Administration Schedule; D020869:Gene Expression Profiling / Q000379:methods; D015972:Gene Expression Regulation, Neoplastic / Q000276:immunology; D006801:Humans; D007371:Interferon-gamma / Q000096:biosynthesis; D008213:Lymphocyte Activation / Q000276:immunology; D016246:Lymphocytes, Tumor-Infiltrating / Q000187:drug effects / Q000276:immunology; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000276:immunology / Q000628:therapy*; D050378:T-Lymphocytes, Regulatory / Q000276:immunology; D015854:Up-Regulation / Q000276:immunology
chemical_list: D018906:Antineoplastic Agents, Alkylating; D019496:Cancer Vaccines; C000593794:GVAX vaccine; D007371:Interferon-gamma; D003520:Cyclophosphamide