Disruption of COX1 and COX2 signaling significantly impairs tumor cell immune evasion.
Major finding: Disruption of COX1 and COX2 signaling significantly impairs tumor cell immune evasion.
Mechanism: COX-driven PGE2 secretion suppresses antitumor immune mediators and induces tumor-promoting inflammation.
Impact: Inhibition of COX may serve as adjuvant therapy with immune-based anticancer therapies.
Active evasion of antitumor immune responses by cancer cells facilitates tumor growth and progression. Although several mechanisms of tumor-mediated immune suppression and evasion have been described, the molecular drivers of this pathway remain poorly understood. Using mouse BrafV600E-driven melanoma cells, Zelenay and colleagues demonstrated that cyclooxygenase (COX)-driven production of prostaglandin E2 (PGE2) is a primary mediator of the proinflammatory signature that enables tumor cells to evade immunosurveillance. COX-dependent secretion of PGE2 by melanoma cells was required for the growth and poor immunogenicity of BrafV600E-mutant melanoma cells in immunocompetent mice and resulted in immunomodulatory effects on bone marrow–derived dendritic cells and macrophages. Double-knockout of the genes encoding COX1 and COX2 eliminated nearly all PGE2 production from tumors and impaired tumor growth in wild-type mice via activation of both adaptive and innate immune responses. COX ablation resulted in impaired accumulation and activation of CD103+ dendritic cells and a shift in the inflammatory profile of myeloid cells, including increased expression of antitumor immune mediators, such as IFNγ, and decreased expression of proinflammatory cytokines, such as IL6. Consistent with these findings, COX-dependent production of PGE2 was necessary for escape from anticancer immunity and tumor formation by multiple types of mouse cancer cell lines, including breast and colorectal cancer cells, indicating a conserved mechanism of tumor-mediated immune suppression. Inhibition of COX synergized with anti–programmed cell death 1 (PD-1) blocking antibody to more effectively inhibit tumor growth in vivo compared with anti–PD-1 alone. Furthermore, in human patients with melanoma, high mRNA expression of the gene encoding COX2 positively correlated with the expression of tumor-promoting inflammatory factors and inversely correlated with IFN-stimulated gene expression, suggesting that COX mediates immune suppression across species. Overall, these data identify COX-driven PGE2 secretion as a critical suppressor of immune surveillance and support the therapeutic potential of COX inhibition in combination with immune checkpoint blockade.
- ©2015 American Association for Cancer Research.