Given the recent clinical validation of

Given the recent clinical validation of immune checkpoint inhibition in NSCLC, it is important to note that EP4 receptors on both tumor and immune protoporphyrin ix may result in a tumor enhancing immunologic environment. Natural killer (NK) cells play a major role in cytokine release, migration, and cytolytic activity. Studies have shown that these functions can be inhibited by PGE2 since NK cells have EP4 receptors [12], [15], [16]. Furthermore, it has been demonstrated that NSCLC patient have high levels of myeloid derived suppressor cells (MDSCs). MDSCs suppress the immune system through multiple mechanisms including the stimulation of T-regulatory cells, drive to type-2 tumor-promoting phenotype, and inhibition of CD4+ and CD8+ T cells and NK cytotoxicity [17], [15] PGE2 interacts with receptors including EP4 on MDSC precursors which stimulates the differentiation and growth of MDSCs [16], [17] Zhang et al. showed that PGE2 also plays a role in Fas signaling which recruits MDSCs, thereby promoting tumor growth in lung cancer [18]. Depletion of MDSCs has been demonstrated in animal models to enhance the efficacy of anti-tumor therapy, including vaccines and chemotherapy [19]. These cells have been shown to inhibit T-cell proliferation and cytotoxic lymphocytes in an MHC- and antigen-independent manner [20]. Myeloid cells expressing similar markers in humans have been found to be increased fivefold in patients with head and neck squamous cell cancer, renal cell cancer, breast cancer, and NSCLC [21]. Depletion of MDSCs has been shown to reduce tumor progression and to improve immune-based cancer therapies [22], [23]. Our observation that nuclear, but not cytoplasmic EP4 expression is associated with different outcomes is interesting. In breast cancer, using the same methods, we did not detect EP4 in the nucleus of malignant cells whereas cytoplasmic EP4 was commonly observed [13]. While G protein-coupled receptors are commonly observed at the plasma membrane, there is a growing body of evidence that nuclear EP receptors have important functions. EP4 has been detected in a perinuclear or nuclear location of porcine cerebral microvascular endothelial cells where it affects gene transcription through a pertussis toxin-sensitive mechanism [24]. While there is evidence that EP4 contributes to malignant behavior in many cancers, the subcellular location and the mechanism underlying these linkages may be context dependent. Thus, cytoplasmic EP4 may drive breast cancer progression whereas nuclear EP4 may drive lung cancer, albeit by a different mechanism. Future studies will be required to understand the mechanism underlying the relationship between nuclear EP4 and poor outcomes in LANSCLC. Novel, orally active selective EP4 antagonists are being developed and tested including AAT-007, which has been evaluated in humans for its analgesic properties [25]. Efficacy and safety in normal volunteers and osteoarthritis associated pain have been established in two U.S. trials. However, efficacy has not been assessed in cancer models or in cancer clinical trials. Our institution will commence the first trial evaluating this drug as a potential antineoplastic in the coming year.