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: Eric R Lutz, Annie A Wu, Elaine Bigelow, Rajni Sharma, Guanglan Mo, Kevin Soares, Sara Solt, Alvin Dorman, Anthony Wamwea, Allison Yager, Daniel Laheru, Christopher L Wolfgang, Jiang Wang, Ralph H Hruban, Robert A Anders, Elizabeth M Jaffee, Lei Zheng
• Journal: Cancer immunology research (Cancer Immunol Res) Vol. 2 Issue 7 Pg. 616-31 (Jul 2014) ISSN: 2326-6074 [Electronic] United States
• PMID: 24942756 (Publication Type: Journal Article, Randomized Controlled Trial, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)
• Copyright: ©2014 American Association for Cancer Research.

Chemical References

• Antineoplastic Agents, Alkylating
• Cancer Vaccines
• GVAX vaccine
• Interferon-gamma
• Cyclophosphamide

Topics

• Adenocarcinoma (genetics, immunology, therapy)
• Antineoplastic Agents, Alkylating (administration & dosage, therapeutic use)
• Cancer Vaccines (therapeutic use)
• Cell Aggregation (immunology)
• Chemotherapy, Adjuvant
• Cyclophosphamide (administration & dosage, therapeutic use)
• Drug Administration Schedule
• Gene Expression Profiling (methods)
• Gene Expression Regulation, Neoplastic (immunology)
• Humans
• Interferon-gamma (biosynthesis)
• Lymphocyte Activation (immunology)
• Lymphocytes, Tumor-Infiltrating (drug effects, immunology)
• Pancreatic Neoplasms (genetics, immunology, therapy)
• T-Lymphocytes, Regulatory (immunology)
• Up-Regulation (immunology)