Abstract：
PD-1 blockade therapy has made great breakthroughs in treatment of multiple solid tumors. However, patients with microsatellite-stable (MSS) colorectal cancer (CRC) respond poorly to anti-PD-1 immunotherapy. Although CRC patients with microstatellite instability (MSI) or microsatellite instability-high (MSI-H) can benefit from PD-1 blockade therapy, there are still some problems such as tumor recurrence. Tumor-associated macrophages (TAMs), most abundant immune components in tumor microenvironment (TME), largely limit the therapeutic efficacy of anti-PD-1 against CRC. The CSF1/CSF1R pathway plays a key role in regulating macrophage polarization, and blocking CSF1R signaling transduction may be a potential strategy to effectively reprogram macrophages and remodel TME. Here, we found that increasing expression of CSF1R in macrophages predicted poor prognosis in CRC cohort. Furthermore, we discovered a novel potent CSF1R inhibitor, PXB17, which significantly reprogramed M2 macrophages to M1 phenotype. Mechanically, PXB17 significantly blocked activation of PI3K/AKT/mTORC1 signaling, resulting in inhibition of cholesterol biosynthesis. Results from 3D co-culture system suggested that PXB17-repolarized macrophages could induce infiltration of CD8+ T lymphocytes in tumors and improve the immunosuppressive microenvironment. In vivo, PXB17 significantly halted CRC growth, with a stronger effect than PLX3397. In particular, PXB17 potently enhanced therapeutic activity of PD-1 mAb in CT-26 (MSS) model and prevented tumor recurrence in MC-38 (MSI-H) model by promoting formation of long-term memory immunity. Our study opens a new avenue for CSF1R in tumor innate and adaptive anti-tumor immunomodulatory activity and suggests that PXB17 is a promising immunotherapy molecule for enhancing the efficacy of PD-1 mAb or reducing tumor recurrence of CRC.
摘要：
PD-1阻断治疗在多发性实体肿瘤的治疗中取得了重大突破。然而,微卫星稳定(MSS)结直肠癌(CRC)患者抗PD-1免疫治疗效果较差.尽管具有微卫星不稳定性（MSI）或微卫星不稳定性高（MSI-H）的CRC患者可以从PD-1阻断治疗中受益，仍存在肿瘤复发等问题。肿瘤相关巨噬细胞（TAMs），肿瘤微环境（TME）中最丰富的免疫成分，在很大程度上限制了抗PD-1对CRC的疗效。CSF1/CSF1R通路在调节巨噬细胞极化中起关键作用,阻断CSF1R信号传导可能是有效重编程巨噬细胞和重塑TME的潜在策略。这里,我们发现,在CRC队列中,巨噬细胞中CSF1R表达的增加预示着预后不良.此外，我们发现了一种新型有效的CSF1R抑制剂，PXB17，其显着将M2巨噬细胞重编程为M1表型。机械上,PXB17显著阻断PI3K/AKT/mTORC1信号的激活，从而抑制胆固醇的生物合成。3D共培养系统的结果表明，PXB17复极化的巨噬细胞可以诱导肿瘤中CD8T淋巴细胞的浸润并改善免疫抑制微环境。在体内,PXB17显著阻止CRC增长，具有比PLX3397更强的效果。特别是,PXB17在CT-26（MSS）模型中有效增强PD-1mAb的治疗活性，并通过促进长期记忆免疫的形成来预防MC-38（MSI-H）模型中的肿瘤复发。我们的研究为CSF1R在肿瘤先天和适应性抗肿瘤免疫调节活性中开辟了一条新途径，并表明PXB17是一种有前途的免疫治疗分子，可增强PD-1mAb的功效或减少CRC的肿瘤复发。
