Cyclooxygenase Inhibition in Cancer Immunotherapy: Combination of Indomethacin with Cancer Vaccines Is Not Always Beneficial

Abstract

Cyclooxygenase (COX)-1, but preferable COX-2 catalyzes the synthesis of PGE2 in several tumors, promoting angiogenesis and a suppressive inflammation in their microenvironments. Different types of cancer vaccines have been combined with COX-2 inhibitors, assuming that its particular mechanism of action will not influence the overall results of the combination. In this research, a possible relationship between the type of cancer vaccine and the outcome of the combination with a COX inhibitor was experimentally addressed. We investigated whether nonsteroidal anti-inflammatory drugs (NSAIDs) affect the immune response to vaccination. Three adjuvants were evaluated for humoral and cellular response using ovalbumin (OVA) as antigen. We evaluated also the impact of indomethacin in five tumor models and the correlation of this effect with the secretion of prostaglandin E2 (PGE2) of these cells. We finally studied the combination of indomethacin with two cancer vaccines in three different experimental settings. COX inhibitor did not interfere with dendritic cells maturation in vitro and did not affect the frequency of splenic immune cell populations in mice. However, the induction of OVA-specific antibodies is affected by the COX inhibitor but its impact on cytotoxic CD8+ T cell response is adjuvant-dependent. In contrast, the antitumor effect of the COX inhibitor in the 3LL-D122 tumor model is not mediated by CD4+ or CD8+ T cells. Interestingly, the in vivo effect observed in this model and others didn’t correlate with levels of PGE2 secretion by the tumor cell lines in vitro. Finally, the combination of a COX inhibitor with cancer vaccines may depend on the type of the cancer vaccine.