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Cyclooxygenase 2 Inhibition Promotes IFN--Dependent Enhancement of Antitumor Responses¹

Sherven Sharma^*,,, Li Zhu^*,, Seok Chul Yang^*, Ling Zhang^*, Jeff Lin^*,, Sven Hillinger^*, Brian Gardner, Karen Reckamp^*, Robert M. Strieter^*,, Min Huang^*,, Raj K. Batra^*,, and Steven M. Dubinett^2,*,,

^* Department of Medicine, Lung Cancer Research Program, and Jonsson Comprehensive Cancer Center, David Geffen School of Medicine, University of California, Los Angeles, CA 90095-1690; and Molecular Gene Medicine Laboratory, Veterans Affairs Greater Los Angeles Healthcare System, Los Angeles, CA 90073

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-, IL-12, and IFN--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- 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.