TREM-1阻断起始的特异性与时机影响其在癌症中的治疗疗效

Overexpression of triggering receptor expressed on myeloid cells 1 (TREM-1) is associated with the immune-suppressive tumor microenvironment (TME) and unfavorable prognosis in pan-cancer. TREM-1 is mainly expressed on neutrophils, monocytes, and macrophages including monocyte-derived macrophages. These cells can play different or even opposite roles in the pathogenesis of cancer. Despite more than two decades of intensive research in the field, the question whether specificity of TREM-1 inhibitor can impact its antitumor efficacy has never been addressed mostly, due to the lack of cell-restricted approaches to TREM-1 blockade. This study aims to determine whether broad or macrophage-specific TREM-1 blockade demonstrates distinct therapeutic efficacy and superior outcomes in cancer models. Ligand-independent TREM-1 inhibitory peptides GF9 and GA31 (the latter in a form of macrophage-targeted lipopeptide complexes, GA31-LPC) were evaluated in animal models of pancreatic cancer. GF9 inhibits TREM-1 on all TREM-1-expressing cells, while GA31-LPC targets TREM-1 predominantly on macrophages. In the Kras (G12D)/Trp53 null/Pdx1-cre (KPC) mouse allograft tumor model established in fully immunocompetent C57BL/6 mice, GF9 and GA31-LPC alone significantly inhibited pancreatic cancer progression. In combination with anti-PD-L1 therapy, GA31-LPC, but not GF9, overcame cancer resistance to PD-L1 checkpoint blockade and synergized with immunotherapy. In PANC-1 xenograft-bearing athymic nude mice with intact innate immunity but lacking T cells, both GF9 and GA31-LPC increased complete response rate and survival when combined with chemotherapy. The effectiveness of these agents was dependent on the timing of TREM-1 blockade initiation relative to chemotherapy. GF9 was effective only when given with but not after chemotherapy. In contrast, GA31-LPC was effective only when given after but not together with chemotherapy. Unexpectedly, GF9 and GA31-LPC alone or combined with anti-PD-L1 and chemotherapy did not exhibit significant antitumor effects in the orthotopic Pan02 syngeneic pancreas tumor allograft model established in C57BL/6 mice. This suggests that selecting the appropriate animal model is critical when developing antitumor agents that target TME. The detailed mechanisms of this paradoxical finding require further investigation for their potential contribution to the long-standing debate whether to activate or inhibit TREM-1 in cancer. In summary, these findings for the first time demonstrate that both inhibitor specificity and timing of treatment initiation are crucial for therapeutic TREM-1 inhibition. This has significant implications for clinical strategies targeting TREM-1, particularly informing tailored treatment approaches for not only pancreatic cancer but also other hard-to-treat tumors.