Abstract
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.
Publication types
-
Research Support, N.I.H., Extramural
-
Research Support, Non-U.S. Gov't
-
Research Support, U.S. Gov't, Non-P.H.S.
-
Research Support, U.S. Gov't, P.H.S.
MeSH terms
-
Adjuvants, Immunologic / antagonists & inhibitors*
-
Adjuvants, Immunologic / physiology
-
Animals
-
CD4-Positive T-Lymphocytes / drug effects
-
CD4-Positive T-Lymphocytes / enzymology
-
CD4-Positive T-Lymphocytes / immunology
-
Cancer Vaccines / administration & dosage
-
Cancer Vaccines / immunology
-
Carcinoma, Lewis Lung / enzymology
-
Carcinoma, Lewis Lung / immunology*
-
Carcinoma, Lewis Lung / prevention & control
-
Cells, Cultured
-
Cyclooxygenase 2
-
Cyclooxygenase 2 Inhibitors
-
Cyclooxygenase Inhibitors / pharmacology*
-
Cytokines / biosynthesis
-
Female
-
Immune Sera / administration & dosage
-
Interferon-gamma / antagonists & inhibitors
-
Interferon-gamma / immunology
-
Interferon-gamma / physiology*
-
Melanoma, Experimental / enzymology
-
Melanoma, Experimental / immunology*
-
Melanoma, Experimental / prevention & control
-
Mice
-
Mice, Inbred C57BL
-
Mice, Knockout
-
Neoplasm Transplantation
-
Prostaglandin-Endoperoxide Synthases / deficiency
-
Prostaglandin-Endoperoxide Synthases / genetics
-
Prostaglandin-Endoperoxide Synthases / metabolism*
-
Pyrazoles / pharmacology
-
Spleen / enzymology
-
Spleen / immunology
-
Spleen / metabolism
-
Sulfonamides / pharmacology
-
Th1 Cells / immunology
-
Th1 Cells / metabolism
Substances
-
4-(5-(4-chlorophenyl)-3-(trifluoromethyl)-1H-pyrazol-1-yl)benzenesulfonamide
-
Adjuvants, Immunologic
-
Cancer Vaccines
-
Cyclooxygenase 2 Inhibitors
-
Cyclooxygenase Inhibitors
-
Cytokines
-
Immune Sera
-
Pyrazoles
-
Sulfonamides
-
Interferon-gamma
-
Cyclooxygenase 2
-
Prostaglandin-Endoperoxide Synthases