Cyclooxygenase 2 inhibition promotes IFN-gamma-dependent enhancement of antitumor responses.
In previous studies, we demonstrated an immune suppressive network in non-small cell lung cancer that is due to overexpression of tumor cyclooxygenase 2 (COX-2). In this study, we assessed the vaccination response to tumor challenge following either pharmacological or genetic inhibition of COX-2 in a murine lung cancer model. Treatment of naive mice with the COX-2 inhibitor, SC-58236, skewed splenocytes toward a type 1 cytokine response, inducing IFN-gamma, IL-12, and IFN-gamma-inducible protein 10, whereas the type 2 cytokines IL-4, IL-5, and IL-10 remained unaltered. Fifty percent of mice receiving SC-58236 and an irradiated tumor cell vaccine completely rejected tumors upon challenge. Those mice that did form tumors following challenge demonstrated a reduced tumor growth. In contrast, all mice either vaccinated with irradiated tumor cells alone or receiving SC-58236 alone showed progressive tumor growth. Studies performed in CD4 and CD8 knockout mice revealed a requirement for the CD4 T lymphocyte subset for the complete rejection of tumors. To determine the role of host COX-2 expression on the vaccination responses, studies were performed in COX-2 gene knockout mice. Compared with control littermates, COX-2(-/-) mice showed a significant tumor growth reduction, whereas heterozygous COX-2(-/+) mice had an intermediate tumor growth reduction following vaccination. In vivo depletion of IFN-gamma abrogated the COX-2 inhibitor-mediated enhancement of the vaccination effect. These findings provide a strong rationale for additional evaluation of the capacity of COX-2 inhibitors to enhance vaccination responses against cancer.
Sharma
Sherven
S
Department of Medicine, Lung Cancer Research Program, David Geffen School of Medicine, University of California-Los Angeles, 10833 LeConte Avenue, Los Angeles, CA 90095-1690, USA.
Zhu
Li
L
Yang
Seok Chul
SC
Zhang
Ling
L
Lin
Jeff
J
Hillinger
Sven
S
Gardner
Brian
B
Reckamp
Karen
K
Strieter
Robert M
RM
Huang
Min
M
Batra
Raj K
RK
Dubinett
Steven M
SM
D000276:Adjuvants, Immunologic / Q000037:antagonists & inhibitors* / Q000502:physiology; D000818:Animals; D015496:CD4-Positive T-Lymphocytes / Q000187:drug effects / Q000201:enzymology / Q000276:immunology; D019496:Cancer Vaccines / Q000008:administration & dosage / Q000276:immunology; D018827:Carcinoma, Lewis Lung / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control; D002478:Cells, Cultured; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D016207:Cytokines / Q000096:biosynthesis; D005260:Female; D007106:Immune Sera / Q000008:administration & dosage; D007371:Interferon-gamma / Q000037:antagonists & inhibitors / Q000276:immunology / Q000502:physiology*; D008546:Melanoma, Experimental / Q000201:enzymology / Q000276:immunology* / Q000517:prevention & control; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009368:Neoplasm Transplantation; D011451:Prostaglandin-Endoperoxide Synthases / Q000172:deficiency / Q000235:genetics / Q000378:metabolism*; D011720:Pyrazoles / Q000494:pharmacology; D013154:Spleen / Q000201:enzymology / Q000276:immunology / Q000378:metabolism; D013449:Sulfonamides / Q000494:pharmacology; D018417:Th1 Cells / Q000276:immunology / Q000378:metabolism; D000096926:Benzenesulfonamides
D000276:Adjuvants, Immunologic; D019496:Cancer Vaccines; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D016207:Cytokines; D007106:Immune Sera; D007371:Interferon-gamma; D011451:Prostaglandin-Endoperoxide Synthases; D011720:Pyrazoles; D013449:Sulfonamides; C119130:4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide; D000096926:Benzenesulfonamides