Pan-TREM-1 versus macrophage-restricted TREM-1 blockade in cancer and other inflammatory pathologies

ABSTRACT Background Triggering receptor expressed on myeloid cells 1 (TREM-1), an inflammation amplifier, is an emerging target in inflammation and oncology. Objective To test my hypothesis that pan-TREM-1 and macrophage-restricted TREM-1 blockades may differ in their efficacy in cancer and other inflammatory diseases. Methods Ligand-independent TREM-1 inhibitory peptides GF9 and GA31 (the latter in a form of macrophage-targeted lipopeptide complexes, GA31-LPC) were used as pan-TREM-1 and macrophage-restricted TREM-1 inhibitors, respectively, to test the hypothesis in multiple animal models of cancer, sepsis, pulmonary inflammation and fibrosis. Results In fully immunocompetent mice, GA31-LPC but not GF9 overcomes pancreatic cancer resistance to PD-L1 blockade and synergizes with immunotherapy. In PANC-1 xenograft-bearing athymic nude mice, GF9 and GA31-LPC both increase complete response rate and survival when combined with chemotherapy but exhibit opposing dependence on timing of treatment initiation. GF9 is effective only when given with but not after chemotherapy. In contrast, GA31-LPC is effective only when given after but not together with chemotherapy. Critical dependence of the therapeutic efficacy of TREM-1 blockade on the type of blocker and treatment timing was also observed in animal models of sepsis and acute lung injury but not fibrosis. Conclusion This study provides the first evidence that pan-TREM-1 and macrophage-restricted TREM-1 blockades may strikingly differ in their therapeutic efficacy depending on the disease, timing of treatment initiation and the type and stage of inflammatory response. This opens new avenues for development of TREM-1-targeting strategies and leads to a new framework for the treatment of cancer and other inflammation-associated diseases.