PARP 抑制与 CD47 阻断协同促进同源重组功能正常肿瘤中肿瘤相关巨噬细胞的吞噬作用

AIMS: 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.

MAIN METHODS: 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. KEY FINDINGS: 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/SIRP signal.

In addition, compared to monotherapy, the concomitant administration of CD47 antibodies with olaparib improved tumor control. SIGNIFICANCE: 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.