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Gangliosides as targets for immunotherapy for pancreatic adenocarcinoma
K U Chu1, M H Ravindranath, A Gonzales
1Roy E. Coats Research Laboratories and the Sonya Valley Ghidossi Vaccine Laboratory of the John Wayne Cancer Institute at Saint John's Health Center, Santa Monica, CA, USA.
Background:
Pancreatic adenocarcinoma cells express gangliosides and sialyl Lewis (sLe) antigens. It is not known whether these carbohydrate antigens can be targeted by immunotherapy. The authors measured the expression of GM(2) and sLe antigens on the surface of pancreatic carcinoma cells and the serum levels of total gangliosides, GM(2), and antiganglioside antibodies in patients with pancreatic carcinoma.
Methods:
Cell surface GM(2) and sLe antigens were measured by cell suspension enzyme linked immunoadsorbent assay (ELISA) in four pancreatic carcinoma cell lines. Sera from 20 pancreatic carcinoma patients and 20 age- and gender-matched healthy volunteers were analyzed for antiganglioside and anti-sLe immunoglobulin (Ig) M titers by ELISA. Serum levels of total gangliosides and GM(2) also were measured.
Results:
All cell lines expressed GM(2) and sLe antigens. When compared with age- and gender-matched volunteers, patients had significantly higher serum levels of total gangliosides (25.6 +/- 9.0 mg/dL vs. 15.6 +/- 2.7 mg/dL; P < 0.001), GM(2) (0.278 +/- 0.415 mg/dL vs. 0.013 +/- 0.018 mg/dL; P = 0.02), ELISA units of anti-GM(2) IgM antibody (368 +/- 95 vs. 155 +/- 25; P = 0.04) and anti-GD(1b) IgM antibody (351 +/- 91 vs. 138 +/- 26; P = 0.03), but not anti-sLe(x) IgM (1389 +/- 345 vs. 1081 +/- 224; P = 0.46) or anti-sLe(a) IgM antibody (1097 +/- 253 vs. 1200 +/- 315; P = 0.80). Patients with unresectable tumors had higher serum levels of total gangliosides compared with patients with resectable tumors, and a serum level > 25 mg/dL was found to correlate significantly with poor overall survival (P < 0.02).
Conclusions:
Increased serum levels of total gangliosides and GM(2) may reflect shedding or release of gangliosides from the surface of tumor cells. Production of IgM antibody against GM(2) and GD(1b) indicates that these gangliosides are immunogenic antigens that may be potential targets for effective active immunotherapy.
Insights
Pancreatic cancer cells express GM2 and sialyl Lewis (sLe) antigens. Patients show elevated serum levels of GM2 and related antibodies, suggesting potential for immunotherapy targeting these carbohydrate antigens.
Area of Science:
- Oncology
- Immunology
- Biochemistry
Background:
- Pancreatic adenocarcinoma cells express gangliosides and sialyl Lewis (sLe) antigens.
- The potential for targeting these carbohydrate antigens with immunotherapy is not well understood.
- This study investigates the expression of GM2 and sLe antigens in pancreatic cancer and their association with serum markers.
Purpose of the Study:
- To measure the expression of GM2 and sLe antigens on pancreatic carcinoma cells.
- To analyze serum levels of total gangliosides, GM2, and antiganglioside antibodies in pancreatic carcinoma patients.
- To evaluate the potential of these antigens as targets for immunotherapy.
Main Methods:
- Enzyme-linked immunosorbent assay (ELISA) was used to measure cell surface GM2 and sLe antigens in four pancreatic carcinoma cell lines.
- Sera from 20 pancreatic carcinoma patients and 20 healthy volunteers were analyzed for immunoglobulin (Ig) M titers against gangliosides and sLe antigens.
- Serum levels of total gangliosides and GM2 were also quantified.
Main Results:
- All tested pancreatic carcinoma cell lines expressed GM2 and sLe antigens.
- Patients exhibited significantly higher serum levels of total gangliosides and GM2 compared to healthy controls.
- Elevated IgM antibody titers against GM2 and GD1b were observed in patients, indicating an immune response to these antigens.
- Higher serum total ganglioside levels correlated with unresectable tumors and poorer overall survival.
Conclusions:
- Increased serum ganglioside levels may result from shedding from tumor cells.
- The production of IgM antibodies against GM2 and GD1b suggests these are immunogenic antigens.
- GM2 and GD1b represent potential targets for active immunotherapy in pancreatic cancer.