TY - JOUR
T1 - Immunotherapy converts nonimmunogenic pancreatic tumors into immunogenic foci of immune regulation
AU - Lutz, Eric R.
AU - Wu, Annie A.
AU - Bigelow, Elaine
AU - Sharma, Rajni
AU - Mo, Guanglan
AU - Soares, Kevin
AU - Solt, Sara
AU - Dorman, Alvin
AU - Wamwea, Anthony
AU - Yager, Allison
AU - Laheru, Daniel
AU - Wolfgang, Christopher L.
AU - Wang, Jiang
AU - Hruban, Ralph H.
AU - Anders, Robert A.
AU - Jaffee, Elizabeth M.
AU - Zheng, Lei
N1 - Funding Information:
This work was supported by the NIH K23 CA148964-01 (to L. Zheng), Johns Hopkins School of Medicine Clinical Scientist Award (to L. Zheng), an American Society of Clinical Oncology Young Investigator Award (to L. Zheng), Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins (to D. Laheru, E.M. Jaffee, E.R. Lutz, and L. Zheng), The National Pancreas Foundation (to L. Zheng), Lefkofsky Family Foundation (to L. Zheng), the NCI SPORE in Gastrointestinal Cancers P50 CA062924 (to E.M. Jaffee, L. Zheng, and E.R. Lutz), Lustgarten Foundation (to E.M. Jaffee and L. Zheng), and the Sol Goldman Pancreatic Cancer Center (to E.R. Lutz and L. Zheng), AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research Award 09-30-14-LUTZ (to E.R. Lutz). E.M. Jaffee is the first recipient of the Dana and Albert "Cubby" Broccoli Endowed Professorship. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
Funding Information:
This work was supported by the NIH K23 CA148964-01 (to L. Zheng), Johns Hopkins School of Medicine Clinical Scientist Award (to L. Zheng), an American Society of Clinical Oncology Young Investigator Award (to L. Zheng), Viragh Foundation and the Skip Viragh Pancreatic Cancer Center at Johns Hopkins (to D. Laheru, E.M. Jaffee, E.R. Lutz, and L. Zheng), The National Pancreas Foundation (to L. Zheng), Lefkofsky Family Foundation (to L. Zheng), the NCI SPORE in Gastrointestinal Cancers P50 CA062924 (to E.M. Jaffee, L. Zheng, and E.R. Lutz), Lustgarten Foundation (to E.M. Jaffee and L. Zheng), and the Sol Goldman Pancreatic Cancer Center (to E.R. Lutz and L. Zheng), AACR-FNAB Fellows Grant for Translational Pancreatic Cancer Research Award 09-30-14-LUTZ (to E.R. Lutz). E.M. Jaffee is the first recipient of the Dana and Albert "Cubby" Broccoli Endowed Professorship.
Publisher Copyright:
© 2014 American Association for Cancer Research.
Copyright:
Copyright 2018 Elsevier B.V., All rights reserved.
PY - 2014/7
Y1 - 2014/7
N2 - 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, granulocytemacrophage 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 vaccineinduced 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.
AB - 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, granulocytemacrophage 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 vaccineinduced 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.
UR - http://www.scopus.com/inward/record.url?scp=84964314430&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=84964314430&partnerID=8YFLogxK
U2 - 10.1158/2326-6066.CIR-14-0027
DO - 10.1158/2326-6066.CIR-14-0027
M3 - Article
C2 - 24942756
AN - SCOPUS:84964314430
VL - 2
SP - 616
EP - 631
JO - Cancer immunology research
JF - Cancer immunology research
SN - 2326-6066
IS - 7
ER -