(639b) Investigating the Impact of TREM2 Variant Dynamics on Apolipoprotein E Binding in Cancer: Insights for Therapeutic Development

Tumor-associated macrophages induce immunosuppression in the tumor microenvironment, presenting a significant limitation for the development of chemotherapeutics. An emerging target for inhibiting immunosuppression is Triggering receptor expressed on myeloid cells 2 (TREM2), a pro-tumorigenic immunosuppressive marker in cancer. TREM2 is a surface receptor whose diverse ligand binding induces macrophage proliferation, survival, phagocytosis, and inflammation. Differential ligand binding implicates TREM2 in a variety of disease states, and interaction with an endogenous protein, Apolipoprotein E (ApoE), has been studied extensively in the context of neurodegenerative disease. The TREM2^R47H variant impairs interactions with ApoE and increases risk of Alzheimer’s disease (AD), while three gene polymorphisms of ApoE, E2, E3, and E4, alter interactions with TREM2 and serve as protective, neutral, and pathogenic variants for AD, respectively. Evidence also supports protective interactions between wild-type (WT) TREM2 and ApoE4 in cancers, suggesting the same conformation of the complex that is deleterious in pro-inflammatory, neurodegenerative disease states may promote inflammatory pathways and rescue immunosuppression in cancer. However, TREM2 cancer-associated variants and their effects on ApoE binding have yet to be explored. Herein, we leverage an in-silico approach based on long timescale molecular dynamics (MD) simulations to analyze TREM2 dynamics in the presence of cancer-associated mutations, probing changes in ApoE binding and informing future de novo drug design. Knowledge of how TREM2 variants interact with ApoE isoforms and deviate from the protective conformation can be applied to the design of a future variant-specific TREM2 allosteric regulator that, without competing with the ApoE binding site, regulates the conformation of TREM2 to recover the protective conformation from TREM2^WT-ApoE4. Consequently, this work provides insights into therapeutic design to target the TREM2-ApoE pathway in macrophage dysfunction in cancer, with applications to other disease states.