TREM-1-mediated modulation of innate immune response in acute and chronic inflammation: Effect of treatment timing and cell specificity on outcome 2223031

Abstract

Abstract Introduction Triggering receptor expressed on myeloid cells 1 (TREM-1) is a promising target in inflammation-related diseases such as cancer, sepsis, acute lung injury (ALI) and pulmonary fibrosis (PF). Myeloid cells, including neutrophils, monocytes and macrophages, may play dual roles in inflammation and diseases depending on the stage and context of the disease process. The aim of this study was to test my hypothesis that the outcome of TREM-1 blockade can be different depending on whether TREM-1 signaling is suppressed in all cells that express TREM-1 (pan-TREM-1 blockade) or only in specific cells (e.g., macrophage-restricted TREM-1 blockade). Methods Animal models of cancer, sepsis, ALI and PF were used to test ligand-independent TREM-1 inhibitory peptides GF9 and GA31 (the latter in a form of macrophage-targeted lipopeptide complexes, GA31-LPC) as pan-TREM-1 and macrophage-restricted TREM-1 inhibitors, respectively. Results In fully immunocompetent mice, macrophage-restricted but not pan-TREM-1 blockade overcomes pancreatic cancer (PC) resistance to PD-L1 blockade and synergizes with immunotherapy. In PC xenograft-bearing athymic nude mice, macrophage-restricted and pan-TREM-1 inhibitors both increase complete response rate and survival when combined with chemotherapy but exhibit opposing dependence on timing of treatment initiation. Pan-TREM-1 treatment is effective only when given with but not after chemotherapy. In contrast, macrophage-restricted TREM-1 treatment is effective only when given after but not together with chemotherapy. Critical dependence of the outcome on the type of TREM-1 inhibitor and treatment timing was also observed in animal models of sepsis and ALI but not PF. Conclusion In summary, this is the first direct evidence that pan-TREM-1 and macrophage-restricted TREM-1 blockades may differ in their therapeutic efficacy depending on the disease, timing of treatment initiation and the type and stage of inflammatory response. Funding Source This work was supported in part by grants R44CA217400 from the National Cancer Institute of (NCI), R43AR078110 from the National Institute of Arthritis and Musculoskeletal and Skin Diseases (NIAMS), R43GM128369 from the National Institute of General Medic Topic Categories Translational and Interventional Immunology (TI)