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Cancer Immunol Res. 2014 Jul;2(7):616-31. doi: 10.1158/2326-6066.CIR-14-0027. Epub 2014 Jun 18.

Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation.

Author information

1
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.
2
Authors' Affiliations: Departments of Oncology, Surgery; The Sidney Kimmel Cancer Center;
3
Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center;
4
Pathology, and.
5
Authors' Affiliations: Departments of Oncology, The Sidney Kimmel Cancer Center; The Skip Viragh Center for Pancreatic Cancer Research and Clinical Care;
6
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.
7
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.
8
Department of Pathology and Laboratory Medicine, University of Cincinnati College of Medicine, Cincinnati, Ohio.
9
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.
10
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.
11
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.

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.

PMID:
24942756
PMCID:
PMC4082460
DOI:
10.1158/2326-6066.CIR-14-0027
[Indexed for MEDLINE]
Free PMC Article

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