Specific inhibition of cyclooxygenase 2 restores antitumor reactivity by altering the balance of IL-10 and IL-12 synthesis

Cyclooxygenase-2 (COX-2), the enzyme at the rate-limiting step of prostanoi d production, has been found to be overexpressed in human lung cancer. To e valuate lung tumor COX-2 modulation of antitumor immunity, we studied the a ntitumor effect of specific genetic or pharmacological inhibition of COX-2 in a murine Lewis lung carcinoma (3LL) model. Inhibition of COX-2 led to ma rked lymphocytic infiltration of the tumor and reduced tumor growth. Treatm ent of mice with anti-PGE(2) mAb replicated the growth reduction seen in tu mor-bearing mice treated with COX-2 inhibitors. COX-2 inhibition was accomp anied by a significant decrement in IL-10 and a concomitant restoration of IL-12 production by APCs, Because the COX-2 metabolite PGE2 is a potent ind ucer of IL-10, it was hypothesized that COX-2 inhibition led to antitumor r esponses by down-regulating production of this potent immunosuppressive cyt okine. In support of this concept, transfer of IL-10 transgenic T lymphocyt es that overexpress IL-10 under control of the IL-2 promoter reversed the C OX-2 inhibitor-induced antitumor response. We conclude that abrogation of C OX-2 expression promotes antitumor reactivity by restoring the balance of I L-10 and IL-12 in vivo.