Pancreatic cancer (PC) is a highly lethal cancer with an urgent need to expand the limited treatment options for patients. Tumor-associated macrophages (TAMs) promote tumor aggressiveness and metastasis. High expression of triggering receptor expressed on myeloid cells 1 (TREM-1) on TAMs directly correlates with poor survival in patients with non-small cell lung cancer (NSCLC). We have previously hypothesized that blockade of TREM-1 could be a promising therapeutic strategy to treat cancer and shown that the novel, ligand-independent TREM-1 inhibitory peptides rationally designed using the signaling chain homooligomerization (SCHOOL) strategy suppress NSCLC growth in vivo. Here, we evaluated the therapeutic potential of these inhibitors in three human PC xenograft mouse models. Administration of SCHOOL peptides resulted in a strong antitumor effect achieving an optimal treatment/control (T/C) value of 19% depending on the xenograft and formulation used and persisting even after treatment was halted. The effect correlated significantly with increased survival and suppressed TAM infiltration. The peptides were well-tolerated when deployed either in free form or formulated into lipopeptide complexes for peptide half-life extension and targeted delivery. Finally, blockade of TREM-1 significantly reduced serum levels of interleukin (IL)-1α, IL-6, and macrophage colony-stimulating factor (M-CSF), but not vascular endothelial growth factor, suggesting M-CSF-dependent antitumor mechanisms. Collectively, these promising data suggest that SCHOOL TREM-1-specific peptide inhibitors have a cancer type independent, therapeutically beneficial antitumor activity and can be potentially used as a stand-alone therapy or as a component of combinational therapy for PC, NSCLC, and other solid tumors.

中文翻译：

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新型TREM-1抑制剂可减轻实验性胰腺癌的肿瘤生长并延长生存期

胰腺癌（PC）是一种高度致死性癌症，迫切需要扩大患者的有限治疗选择。肿瘤相关巨噬细胞（TAMs）促进肿瘤侵袭性和转移。TAM的髓样细胞1（TREM-1）上表达的触发受体的高表达与非小细胞肺癌（NSCLC）患者的不良生存率直接相关。我们先前曾假设，阻断TREM-1可能是治疗癌症的一种有前途的治疗策略，并表明使用信号链均聚（SCHOOL）策略合理设计的新颖，不依赖配体的TREM-1抑制肽可以抑制NSCLC在体内的生长。在这里，我们评估了这些抑制剂在三种人PC异种移植小鼠模型中的治疗潜力。施用SCHOOL肽可产生强大的抗肿瘤作用，从而实现最佳治疗/控制（T / C）值（取决于所用异种移植物和配方）的19％，即使在治疗后仍可持久。该效果与存活率的增加和TAM浸润的抑制显着相关。当以自由形式或配制为肽半衰期延长和靶向递送的脂肽复合物时，该肽具​​有良好的耐受性。最后，阻断TREM-1可显着降低血清白介素（IL）-1α，IL-6和巨噬细胞集落刺激因子（M-CSF）的水平，但不能降低血管内皮生长因子，提示M-CSF依赖的抗肿瘤机制。总的来说，这些有前途的数据表明SCHOOL TREM-1特异性肽抑制剂具有与癌症类型无关的作用，