Pancreatic adenocarcinoma upregulated factor serves as adjuvant by activating dendritic cells through stimulation of TLR4.

Tae Heung Kang,Yeong-Min Park,T.-C Wu,Hee Dong Han,Jaemin Lee,In Duk Jung,Hyun-Ju Lee,Young Seob Kim,Seokho Kim,Sang Seok Koh,Seung-Hyun Lee,Benjamin Yang,Je-Jung Lee

doi:10.18632/oncotarget.4859

Abstract

Dendritic cell (DC) based cancer vaccines represent a promising immunotherapeutic strategy against cancer. To enhance the modest immunogenicity of DC vaccines, various adjuvants are often incorporated. Particularly, most of the common adjuvants are derived from bacteria. In the current study, we evaluate the use of a human pancreatic cancer derived protein, pancreatic adenocarcinoma upregulated factor (PAUF), as a novel DC vaccine adjuvant. We show that PAUF can induce activation and maturation of DCs and activate NFkB by stimulating the Toll-like receptor signaling pathway. Furthermore, vaccination with PAUF treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice. Finally, we demonstrated that PAUF mediated DC activation and immune stimulation are dependent on TLR4. Our data provides evidence supporting PAUF as a promising adjuvant for DC based therapies, which can be applied in conjunction with other cancer therapies. Most importantly, our results serve as a reference for future investigation of human based adjuvants.

Highlights

Dendritic cell (DC) based cancer vaccines represent a promising approach [1, 2]
Vaccination with pancreatic adenocarcinoma upregulated factor (PAUF) treated DCs pulsed with E7 or OVA peptides leads to generation of E7 or OVA-specific CD8+ T cells and memory T cells, which correlate with long term tumor protection and antitumor effects against TC-1 and EG.7 tumors in mice
DCs incubated with PAUF express higher levels of maturation surface markers CD40, CD80, CD86, and major histocompatibility (MHC) class I compared to untreated DCs at a level similar to LPS treated DCs (Figures 1B–1C)

Summary

Introduction

Dendritic cell (DC) based cancer vaccines represent a promising approach [1, 2]. DCs are the most potent antigen-presenting cells, in priming CD8+ T cell mediated immune responses, due to the expressions of major histocompatibility (MHC) class I and costimulatory molecules [3]. To increase the antitumor immune responses generated by DC vaccines, adjuvants should be incorporated. The conventional adjuvants include cytokines, Tolllike receptor ligands and heat shock proteins. Cytokines such as interleukin-2 (IL-2) and granulocyte-macrophage colony-stimulating factor (GM-CSF) have been used as www.impactjournals.com/oncotarget adjuvants in cancer vaccines [5, 6]. Most of the current cancer vaccine adjuvants are derived from bacteria, and are used to elicit innate immune responses mostly by stimulating the Toll-like receptors (TLR) [7]. Numerous adjuvants have been incorporated into DC vaccines, such as Tumor necrosis factor-related activation-induced cytokine (TRANCE) and OK-432 [9, 10], a bacterial adjuvant. DC vaccines can be used in combination with other therapies, such as using chemotherapies to modulate the tumor microenvironment, to elicit stronger antitumor immune responses [11]

Methods

Results

Conclusion