The Role of Prostaglandin E(2) in Tumor-Associated Immunosuppression

Abstract

Tumor-associated inflammation can create an immunosuppressive microenvironment allowing tumor cells to escape immunosurveillance. Inhibiting immunosuppression remains one of the major challenges in cancer immunotherapy via checkpoint inhibitors. Recent preclinical data from the Reis e Sousa group may provide a strong rationale for developing new therapeutics to subvert tumor-induced immunosuppression via prostaglandin inhibition.

Fig. 1

Models illustrating a role of pro-inflammatory PGE₂ in inducing a shift from anti-tumor to immunosuppressive responses within tumor microenvironments. Arachidonic acid (AA) constitutes the phospholipid domain of most cell membranes, liberated by cytoplasmic phospholipase A₂ (cPLA₂). COX enzymes convert free AA to an intermediate PGH₂ that is sequentially metabolized to prostanoids, including prostaglandins (PGs) and thromboxanes (TXs) via specific PG and TX synthases. PGE₂ produced by tumor epithelial cells and/or their surrounding stromal cells might induce immunosuppression through 1) inhibition of DC differentiation, infiltration, and activation; 2) induction of monocytes into an M2 macrophage phenotype and inhibiting LPS-induced TNFα and IL-12 in M1 macrophages; and 3) inducing MDSC differentiation and production of arginase I. T cell activation requires antigen-specific TCR stimulation and activation of an antigen-independent costimulatory receptor (CD28). PD-1 and CTLA-4 are induced in effector T cells and PD-L1 expression is elevated in various human cancer cells. Interaction of PD-1 with PD-L1 inhibits effector T cell activation and induces effector T cell apoptosis. Malignant cells can escape immunosurveillance by impairing CD8⁺ T cell cytotoxicity through co-inhibitory receptors such as PD-1 and CTLA-4. Tumor-associated immunosuppression can diminish the anti-tumor effects of PD-1, PD-L1, and CTLA-4 antibodies.