Tumor-associated macrophages induce immunosuppression in the tumor microenvironment, presenting a significant limitation for the development of immunotherapeutics. An emerging target for inhibiting immunosuppression is Triggering receptor expressed on myeloid cells 2 (TREM2), a pro-tumorigenic immunosuppressive marker in cancer and a hallmark of anti-inflammatory M2 macrophages. TREM2 is a transmembrane surface receptor whose diverse ligand binding induces heterogeneous macrophage proliferation, survival, phagocytosis, and inflammation. Differential TREM2 binding with lipoproteins, phospholipids, and many other ligands alter downstream signaling and macrophage polarization, implicating TREM2 in a variety of inflammatory disease states. Though several TREM2 and ligand variants have been studied extensively in the context of neurodegeneration, the effect of cancer associated variants has yet to be explored. Herein, we present an in-silico approach to analyze the effect of cancer associated variants on the structure and dynamics of TREM2 and two experimentally verified direct ligands, Apolipoprotein E (ApoE) and Cyclophilin A (CypA). Following, we identify how the presence of variants leads to changes in ligand binding location and affinity, with implications for downstream signaling and macrophage function. Identification of variant receptor-ligand conformations will be instrumental in the design process to modulate pro- or anti-inflammatory signaling. Consequently, this work fills a critical sequence-to-structure knowledge gap to inform future structure-to-signaling TREM2-mediated therapeutic design in cancer and other inflammatory disease states.
