Combination targeting of myeloid cell stromal checkpoints 4738

Abstract Description Background Suppressive myeloid cells in the tumor microenvironment (TME) limit anti-tumor immunity. Immunoglobulin-like transcript 3 (ILT3) and leukocyte-associated receptor 1 (LAIR1) are inhibitory immunoreceptors expressed on tumor-associated myeloid cells that bind to the extracellular matrix (ECM) ligands fibronectin (FN) and collagen (COL), respectively. NGM831 binds to ILT3 and blocks its interaction with FN, while NGM438 binds to LAIR1 and blocks its interaction with COL. Because ILT3 and LAIR1 are both highly expressed on suppressive myeloid cells and bind to ECM ligands that are co-expressed in the TME, we investigated the effects of dual blockade on myeloid cell phenotype. Methods Primary monocyte-derived dendritic cells were polarized to a tolerogenic phenotype and cultured on FN and COL to model the suppressive tumor stroma. The effects of single and dual blockade of ILT3 and LAIR1 were assessed by measuring cytokine secretion, gene expression, and surface marker expression in the presence of NGM831 and/or NGM438. Results When both ECM ligands were present, dual blockade of ILT3 and LAIR1 had synergistic effects on myeloid cell activation and repolarization. Thus, blockade of both “stromal checkpoints” may be required to fully overcome the immunosuppressive effects of the tumor stroma. These data provide support for combination targeting of stromal checkpoint inhibitors. A Phase 1 trial of NGM831 and NGM438 with pembrolizumab was initiated in August 2023. Topic Categories Tumor Immunology: Cellular Responses and Tumor Microevironment (TIME)