摘要
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 Galα1-3Galβ1-4Glc NAc-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 Ig G 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.
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 Galα1-3Galβ1-4Glc NAc-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 Ig G 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.
基金
Supported by Ministry of Education,Sports and Culture of Japan to M.T.,No.25462129
