Published online Oct 28, 2015. doi: 10.3748/wjg.v21.i40.11396
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
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.
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.