Cyclooxygenase (COX)-2, one of the rate-limiting enzymes for production of prostanoids, is commonly upregulated in numerous cancers, and together with prostaglandin E2 (PGE2), has been implicated in several aspects of malignant growth including proliferation, angiogenesis, and invasion. We found that COX-dependent production of PGE2 by melanoma cells dominantly and primarily enables progressive tumor growth via immune escape. Melanoma cells, unable to produce PGE2 by means of genetic ablation of COX or prostaglandin E synthase, formed spontaneously regressing tumors in immune-competent mice but progressive tumors in immune-deficient hosts. By contrast, their PGE2-competent parental lines grew progressively and irrespectively of the presence of a fully competent immune system, demonstrating an essential role for PGE2 in immune evasion. Importantly, PGE2-dependent immune escape was crucial not only in melanoma but also in colorectal and breast cancer models, arguing that this is a general mechanism for subversion of anticancer immunity. COX deficiency in cancer cells was associated with a marked shift in the inflammatory signature at the tumor site characterized by lower expression of cancer-promoting factors and concomitant increase in several mediators typically associated with antitumor immunity. These drastic changes in the inflammatory nature of the tumor microenvironment due to reduced PGE2 levels suggested that COX inhibitors could be used to potentiate immune-dependent control. Indeed, we found that combining COX-inhibitors, such as aspirin, with anti-PD-1 blockade synergistically promoted growth control of tumors poorly responsive to either monotherapy. Finally, analysis of publicly available human melanoma datasets revealed a remarkable conservation of the COX-driven mouse inflammatory signature suggesting that COX activity might be a driver of immune suppression across species.
Citation Format: Santiago Zelenay. Manipulating inflammation to raise cancer immunogenicity [abstract]. In: Proceedings of the Second CRI-CIMT-EATI-AACR International Cancer Immunotherapy Conference: Translating Science into Survival; 2016 Sept 25-28; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(11 Suppl):Abstract nr IA29.