Background: Despite many efforts to effectively treat PDAC, PDAC carries one of the highest mortality rates of all major cancers. Thus, there is a critical unmet need to develop novel approaches to improve the clinical outcome of PDAC. It is well known that many cancers, including PDAC, generate a local TME that allows cancer to escape normal immune surveillance. Phosphatidylserine (PS), a negatively charged phospholipid that is abundant on the cancer cell membrane and with known actions to promote the secretion of immunomodulatory proteins, may provide a mechanism to regulate the TME. This study explored that possibility. Methods: MΦ differentiation and polarization were assessed by Western blotting and flow cytometric approaches. PS exposure and surface markers were analyzed by flow cytometry. Protein–protein and protein–lipid interactions were analyzed by immunofluorescence and enzyme-linked immunosorbent assay (ELISA). Phospholipid and SapC-DOPG treatment were employed to assess target protein functions in MΦ polarization, tumor growth, and survival in subcutaneous and orthotopic tumor models. The PK-PD and safety of SapC-DOPG were tested on orthotopic mouse models. Results: Our studies show that PDAC secretes Hsp70 that stimulates the MΦ polarization to the immunosuppressive M2 phenotype. We found that high surface PS on cancer cells correlates with increased secretion of Hsp70 and is associated with higher MΦ differentiation activity in vitro and in vivo. Furthermore, blocking cancer cell-secreted Hsp70 with SapC-DOPG reverses the immune suppression and reduces tumor growth. Conclusions: These preclinical results reveal a novel immunotherapeutic approach to potentially improve the outcome of PDAC treatment in humans.
背景：尽管已付出诸多努力以有效治疗胰腺导管腺癌（PDAC），但该病在所有主要癌症中仍具有最高的死亡率之一。因此，开发新方法以改善PDAC的临床预后存在迫切且未满足的需求。众所周知，包括PDAC在内的多种癌症会形成局部肿瘤微环境（TME），使癌细胞得以逃避免疫监视。磷脂酰丝氨酸（PS）作为一种带负电荷的磷脂，在癌细胞膜上含量丰富，已知具有促进免疫调节蛋白分泌的作用，可能为调控TME提供机制。本研究探讨了这一可能性。 方法：通过蛋白质印迹法和流式细胞术评估巨噬细胞（MΦ）的分化和极化。采用流式细胞术分析PS暴露情况及表面标志物。通过免疫荧光和酶联免疫吸附试验（ELISA）分析蛋白质-蛋白质及蛋白质-脂质相互作用。在皮下和原位肿瘤模型中，应用磷脂及SapC-DOPG处理以评估靶蛋白在MΦ极化、肿瘤生长和生存中的作用。通过原位小鼠模型测试SapC-DOPG的药代动力学-药效学特性及安全性。 结果：研究表明，PDAC分泌的热休克蛋白70（Hsp70）可刺激MΦ极化为免疫抑制性的M2表型。我们发现癌细胞表面高表达的PS与Hsp70分泌增加相关，并在体外和体内实验中与更高的MΦ分化活性相关联。此外，使用SapC-DOPG阻断癌细胞分泌的Hsp70可逆转免疫抑制并抑制肿瘤生长。 结论：这些临床前研究结果揭示了一种新型免疫治疗方法，有望改善人类PDAC的治疗效果。
肿瘤(癌症)患者之家