Background:We have previously reported engineered macrophages (MacTriggers) that can accelerate the release of tumor necrosis factor-α in response to M2 polarization. MacTriggers are characterized by two original characteristics of macrophages: (1) migration to tumors; and (2) polarization to the M2 phenotype in tumors. Intravenously administered MacTriggers efficiently accumulated in the tumors and induced tumor-specific inflammation. This study reports a novel methodology for enhancing the anti-tumor effects of immune checkpoint inhibitors (ICIs).Results:In this study, we newly found that the intravenously administered MacTriggers in BALB/c mouse models upregulated the expression levels of immune checkpoint proteins, such as programmed cell death (PD)-1 in CD8+T cells and PD-ligand 1 (PD-L1) in cancer cells and macrophages. Consequently, in two ICI-resistant tumor-inoculated mouse models, the combined administration of MacTrigger and anti-PD-1 antibody (aPD-1) synergistically inhibited tumor growth, whereas monotherapy with aPD-1 did not exhibit anti-tumor effects. This synergistic effect was mainly from aPD-1 enhancing the tumor-attacking ability of CD8+T cells, which could infiltrate into the tumors following MacTrigger treatment. Importantly, no side effects were observed in normal tissues, particularly in the liver and spleen, indicating that the MacTriggers did not enhance the aPD-1 reactivity in normal tissues. This specificity was from the MacTriggers not polarizing to the M2 phenotype in normal tissues, thereby avoiding inflammation and increased PD-1/PD-L1 expression. MacTriggers could enhance aPD-1 reactivity only in tumors following tumor-specific inflammation induction.Conclusions:Our findings suggest that the MacTrigger and aPD-1 combination therapy is a novel approach for potentially overcoming the current low ICI response rates while avoiding side effects.
背景：我们先前报道了工程化巨噬细胞（MacTriggers），其能够响应M2极化而加速肿瘤坏死因子-α的释放。MacTriggers具有巨噬细胞的两大固有特性：(1)向肿瘤迁移；(2)在肿瘤中极化为M2表型。静脉注射的MacTriggers能有效富集于肿瘤组织并诱导肿瘤特异性炎症。本研究报道了一种增强免疫检查点抑制剂抗肿瘤效应的新方法。 结果：本研究发现，在BALB/c小鼠模型中，静脉注射的MacTriggers可上调免疫检查点蛋白的表达水平，包括CD8+T细胞中的程序性细胞死亡蛋白-1及癌细胞与巨噬细胞中的PD-配体1。因此，在两种ICI耐药肿瘤移植小鼠模型中，MacTrigger与抗PD-1抗体联合给药能协同抑制肿瘤生长，而单独使用抗PD-1抗体则未显示抗肿瘤效应。这种协同效应主要源于抗PD-1抗体增强了CD8+T细胞的肿瘤攻击能力，这些T细胞在MacTrigger治疗后能浸润至肿瘤组织。值得注意的是，正常组织（特别是肝脏和脾脏）中未观察到副作用，表明MacTriggers未增强正常组织对抗PD-1抗体的反应性。这种特异性源于MacTriggers在正常组织中不发生M2表型极化，从而避免了炎症反应及PD-1/PD-L1表达上调。MacTriggers仅在诱导肿瘤特异性炎症后，于肿瘤组织中增强抗PD-1抗体的反应性。 结论：我们的研究结果表明，MacTrigger与抗PD-1抗体联合疗法是一种创新策略，有望在避免副作用的同时，突破当前免疫检查点抑制剂低应答率的瓶颈。
肿瘤(癌症)患者之家