The strength of the inflammatory signature in the tumor microenvironment (TME) is a critical determinant of the host anti-tumor immune response. Type I Interferon (IFN) production by tumor tissue directly or by tumor associated macrophages and dendritic cells can increase the inflammatory potential of the TME and significantly increase spontaneous cell mediated anti-tumor responses (e.g. CD8 T and NK). The cGAS/STING innate immune sensor system has recently been uncovered as a major driver of IFN production in the TME and this has generated considerable interest in pharmacologic stimulation of cGAS/STING alone and in conjunction with other immuno-therapies. However, how tumors may evade or minimize cGAS/STING responses in response to agonists is an open question. We have found that activators of the cGAS/STING axis trigger a coincident prostaglandin PGE2 response which potently suppresses STING dependent IFN production through the specific EP3 receptor. This PGE2 autocrine/paracrine negative feedback loop likely functions to limit the extent of cGAS/STING IFN production both from the tumor tissue itself, and from tumor associated innate immune cells. This preliminary observation is also notable in light of an extensive tumor biology literature demonstrating that numerous tumor types can constitutively secrete high levels of PGE2 that is associated with tumor aggressiveness and poor patient prognosis. Such deleterious effects of tumor secreted PGE2 may be due in part to suppression of innate immune surveillance by cGAS/STING. The overall goal of this project is to understand the mechanism of PGE2 production during cGAS/STING responses in tumors, and to determine whether inhibition of one PGE2 receptor, EP3, can contribute to tumor control in in vivo pre clinical models.
In AIM 1 we will define the pathways governing PGE2 production in primary immune cells and tumor cell lines and ascertain whether regulation of cGAS/STING by PGE2 /EP3 is a common feature of tumors from multiple tissue types.
In AIM2 we will use established animal tumor models to test the efficacy of pharmacologically inhibiting the PGE2/EP3 feedback circuit on cGAS/STING activation and IFN responses in the TME.
In the correct circumstances, human tumors can be detected by the human immune system and cleared from the body. However, many tumors can actively suppress the normal immune response against them. One way tumors suppress the immune response is by producing specialized lipids called prostaglandins, and we have found that one way these prostaglandins can act is by inhibiting an immune surveillance protein called STING.
