Eph receptors activate myeloid checkpoint receptor LILRB5 to support tumor development

Abstract Immunosuppressive myeloid cells are critical obstacles to T cell-centered immune checkpoint blockade therapies, which have been successful in treating a fraction of cancer patients. How tumor cells interact with myeloid cells to regulate immune responses and tumor development is unclear. Here, we report that certain membrane tyrosine kinase Eph receptors, including EphA7 and EphB1, specifically bind the immune inhibitory receptors leukocyte immunoglobin like receptor family B 5 (LILRB5) and leukocyte immunoglobin like receptor family B 2 (LILRB2). These Eph receptors induce LILRB5-mediated signaling activation, and LILRB5 also activates Eph receptor signaling. Activation of LILRB5 promoted immunosuppressive marker expression and inhibited activating marker expression on myeloid cells from cancer patients in vitro. Upon myeloid cell-specific expression of LILRB5 in transgenic mice, the interaction between the Eph receptor on tumor cells and LILRB5 on myeloid cells led to increased tumor growth, increased immunosuppressive myeloid cells, and decreased frequencies of functional T cells compared to control mice. Eph-induced LILRB5 signaling and functions were reversed by LILRB5 blockade. In sum, certain Eph receptors functionally interact with the myeloid checkpoint receptor LILRB5 resulting in bi-directional signaling, and LILRB5 plays an important role in supporting immunosuppressive myeloid cells and sustaining tumor development.