Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Department of Medical Records, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
Life Sci. 2023 Aug 1;326:121790. doi: 10.1016/j.lfs.2023.121790. Epub 2023 May 19.
PARP inhibitors (PARPi) are known to exert anti-tumor effects in patients with BRCA-mutated (BRCAmut) or homologous recombination (HR)-deficient cancer, but recent clinical investigations have suggested that this treatment may also be beneficial in patients with HR-proficient tumors. In this study, we aimed to investigate how PARPi exerts anti-tumor effects in non-BRCAmut tumors.
BRCA wild-type, HR-deficient-negative ID8 and E0771 murine tumor cells were treated in vitro and in vivo with olaparib, a clinically approved PARPi. The effects on tumor growth in vivo were determined in immune-proficient and -deficient mice and alterations of immune cell infiltrations were analyzed with flow cytometry. Tumor-associated macrophages (TAMs) were further investigated with RNA-seq and flow cytometry. In addition, we confirmed olaparib's effect on human TAMs.
Olaparib did not affect HR-proficient tumor cell proliferation and survival in vitro. However, olaparib significantly decreased tumor growth in C57BL/6 and SCID-beige mice (defective in lymphoid development and NK cell activity). Olaparib increased macrophage numbers in the tumor microenvironment, and their depletion diminished the anti-tumor effects of olaparib in vivo. Further analysis revealed that olaparib improved TAM-associated phagocytosis of cancer cells. Notably, this enhancement was not solely reliant on the "Don't Eat Me" CD47/SIRPα signal. In addition, compared to monotherapy, the concomitant administration of αCD47 antibodies with olaparib improved tumor control.
Our work provides evidence for broadening the application of PARPi in HR-proficient cancer patients and paves the way for developing novel combined immunotherapy to upgrade the anti-tumor effects of macrophages.
聚腺苷二磷酸核糖聚合酶抑制剂（PARPi）已知在 BRCA 突变（BRCAmut）或同源重组（HR）缺陷型癌症患者中发挥抗肿瘤作用，但最近的临床研究表明，这种治疗方法可能对 HR 功能正常的肿瘤患者也有益。在这项研究中，我们旨在研究 PARPi 如何在非 BRCAmut 肿瘤中发挥抗肿瘤作用。
BRCA 野生型、HR 缺陷阴性 ID8 和 E0771 鼠肿瘤细胞在体外和体内用奥拉帕利（一种临床批准的 PARPi）进行治疗。在免疫功能正常和缺陷的小鼠中测定体内肿瘤生长的影响，并通过流式细胞术分析免疫细胞浸润的变化。进一步用 RNA-seq 和流式细胞术研究肿瘤相关巨噬细胞（TAMs）。此外，我们还证实了奥拉帕利对人 TAMs 的作用。
奥拉帕利在体外不影响 HR 功能正常的肿瘤细胞增殖和存活。然而，奥拉帕利显著降低了 C57BL/6 和 SCID-beige 小鼠（淋巴发育和 NK 细胞活性缺陷）肿瘤的生长。奥拉帕利增加了肿瘤微环境中的巨噬细胞数量，其耗竭减少了奥拉帕利在体内的抗肿瘤作用。进一步分析表明，奥拉帕利改善了 TAM 相关的癌细胞吞噬作用。值得注意的是，这种增强不仅仅依赖于“不要吃我”CD47/SIRPα信号。此外，与单药治疗相比，同时给予αCD47 抗体和奥拉帕利可改善肿瘤控制。
我们的工作为拓宽 PARPi 在 HR 功能正常的癌症患者中的应用提供了证据，并为开发新的联合免疫疗法以增强巨噬细胞的抗肿瘤作用铺平了道路。
