Cyclooxygenase-2 inhibitor enhances the efficacy of a breast cancer vaccine: role of IDO.
We report that administration of celecoxib, a specific cyclooxygenase-2 (COX-2) inhibitor, in combination with a dendritic cell-based cancer vaccine significantly augments vaccine efficacy in reducing primary tumor burden, preventing metastasis, and increasing survival. This combination treatment was tested in MMTV-PyV MT mice that develop spontaneous mammary gland tumors with metastasis to the lungs and bone marrow. Improved vaccine potency was associated with an increase in tumor-specific CTLs. Enhanced CTL activity was attributed to a significant decrease in levels of tumor-associated IDO, a negative regulator of T cell activity. We present data suggesting that inhibiting COX-2 activity in vivo regulates IDO expression within the tumor microenvironment; this is further corroborated in the MDA-MB-231 human breast cancer cell line. Thus, a novel mechanism of COX-2-induced immunosuppression via regulation of IDO has emerged that may have implications in designing future cancer vaccines.
Basu
Gargi D
GD
Mayo Clinic College of Medicine, and Mayo Clinic Arizona, 13400 East Shea Boulevard, Scottsdale, AZ 85259, USA.
Tinder
Teresa L
TL
Bradley
Judy M
JM
Tu
Tony
T
Hattrup
Christine L
CL
Pockaj
Barbara A
BA
Mukherjee
Pinku
P
D000276:Adjuvants, Immunologic / Q000627:therapeutic use*; D000818:Animals; D019496:Cancer Vaccines / Q000276:immunology / Q000627:therapeutic use*; D000068579:Celecoxib; D045744:Cell Line, Tumor; D016861:Cyclooxygenase Inhibitors / Q000627:therapeutic use*; D004195:Disease Models, Animal; D005260:Female; D006801:Humans; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase / Q000096:biosynthesis / Q000235:genetics / Q000378:metabolism*; D008297:Male; D015674:Mammary Neoplasms, Animal / Q000201:enzymology / Q000235:genetics / Q000276:immunology* / Q000628:therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D011720:Pyrazoles / Q000627:therapeutic use*; D013449:Sulfonamides / Q000627:therapeutic use*
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D016861:Cyclooxygenase Inhibitors; D050503:Indoleamine-Pyrrole 2,3,-Dioxygenase; D011720:Pyrazoles; D013449:Sulfonamides; D000068579:Celecoxib