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Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Oct 28, 2015; 21(40): 11396-11410
Published online Oct 28, 2015. doi: 10.3748/wjg.v21.i40.11396
Cancer immunotherapy for pancreatic cancer utilizing α-gal epitope/natural anti-Gal antibody reaction
Masahiro Tanemura, Eiji Miyoshi, Hiroaki Nagano, Hidetoshi Eguchi, Katsuyoshi Matsunami, Kiyomi Taniyama, Nobutaka Hatanaka, Hiroki Akamatsu, Masaki Mori, Yuichiro Doki
Masahiro Tanemura, Hiroki Akamatsu, Department of Surgery, Osaka Police Hospital, 10-31 Kitayamacho Tennoujiku, Osaka 543-0035, Japan
Eiji Miyoshi, Department of Molecular Biochemistry and Clinical Investigation, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Hiroaki Nagano, Department of Digestive Surgery and Surgical Oncology, Yamaguchi University Graduate School of Medicine, Yamaguchi 755-8505, Japan
Hidetoshi Eguchi, Masaki Mori, Yuichiro Doki, Department of Gastroenterological Surgery, Osaka University Graduate School of Medicine, Osaka 565-0871, Japan
Katsuyoshi Matsunami, Department of Pharmacognosy, Graduate School of Biomedical and Health Sciences, Hiroshima University, Hiroshima 734–8553, Japan
Kiyomi Taniyama, Nobutaka Hatanaka, Department of Surgery and Institute for Clinical Research, National Hospital Organization Kure Medical Center and Chugoku Cancer Center, Hiroshima 737-0023, Japan
Author contributions: Tanemura M, Nagano H and Miyoshi E designed the research; Eguchi H and Matsunami K performed the research; Tanemura M wrote the paper; Mori M and Doki Y critically reviewed the paper; Taniyama K, Hatanaka N and Akamatsu H critically revised the paper.
Supported by Ministry of Education, Sports and Culture of Japan to M. T., No. 25462129.
Conflict-of-interest statement: The authors have no conflict of interest related to the manuscript.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Masahiro Tanemura, MD, PhD, Department of Surgery, Osaka Police Hospital, 10-31 Kitayamacho Tennoujiku, Osaka 543-0035, Japan. tanemuram@oph.gr.jp
Telephone: +81-6-67716051 Fax: +81-6-67752838
Received: May 4, 2015
Peer-review started: May 9, 2015
First decision: June 2, 2015
Revised: July 2, 2015
Accepted: August 30, 2015
Article in press: August 31, 2015
Published online: October 28, 2015
Processing time: 171 Days and 23.9 Hours
Abstract

Pancreatic ductal adenocarcinoma (PDAC) has the poorest prognosis of all malignancies and is largely resistant to standard therapy. Novel treatments against PDAC are desperately needed. Anti-Gal is the most abundant natural antibody in humans, comprising about 1% of immunoglobulins and is also naturally produced in apes and Old World monkeys. The anti-Gal ligand is a carbohydrate antigen called “α-gal epitopes” with the structure Galα1-3Galβ1-4GlcNAc-R. These epitopes are expressed as major carbohydrate antigens in non-primate mammals, prosimians, and New World monkeys. Anti-Gal is exploited in cancer vaccines to increase the immunogenicity of antigen-presenting cells (APCs). Cancer cells or PDAC tumor lysates are processed to express α-gal epitopes. Vaccination with these components results in in vivo opsonization by anti-Gal IgG in PDAC patients. The Fc portion of the vaccine-bound anti-Gal interacts with Fcγ receptors of APCs, inducing uptake of the vaccine components, transport of the vaccine tumor membranes to draining lymph nodes, and processing and presentation of tumor-associated antigens (TAAs). Cancer vaccines expressing α-gal epitopes elicit strong antibody production against multiple TAAs contained in PDAC cells and induce activation of multiple tumor-specific T cells. Here, we review new areas of clinical importance related to the α-gal epitope/anti-Gal antibody reaction and the advantages in immunotherapy against PDAC.

Keywords: Pancreatic cancer; Immunotherapy; Cancer antigen; MUC1; α-gal epitopes; Cancer vaccine; Cancer stem cell; Carbohydrate research

Core tip: The goal of cancer immunotherapy is to elicit an immune response against autologous tumors and to induce multiple T cell clones against multiple tumor-associated antigens. To establish effective, next-generation immunotherapy toward pancreatic ductal adenocarcinoma (PDAC), we focus on the strong interaction between the natural human antibody, anti-Gal, and carbohydrate antigens called “α-gal epitopes”. Here, we review the literature on the distribution of natural anti-Gal antibody and its ligand in mammals and characterization of the immunosuppressive microenvironment of PDAC tumors, which is a major obstacle against effective clinical immunotherapies. We also discuss immunotherapeutic strategies using the α-gal epitope/anti-Gal antibody reaction.