PARP inhibition synergizes with CD47 blockade to promote phagocytosis by tumor-associated macrophages in homologous recombination-proficient tumors

  • Life Sci. 2023 May 19;121790. doi: 10.1016/j.lfs.2023.121790.
Yangyang Liu  1 ,  Rui Xue  1 ,  Xixi Duan  1 ,  Xiaoping Shang  2 ,  Ming Wang  1 ,  Fazhan Wang  1 ,  Linyu Zhu  1 ,  Lijing Zhang  1 ,  Xin Ge  3 ,  Xianlan Zhao  4 ,  Hongjun Guo  4 ,  Zhihong Wang  5 ,  Lindong Zhang  6 ,  Xiang Gao  6 ,  Airong Shen  6 ,  Yuqiao Sheng  7 ,  Zhihai Qin  8
Affiliations
  • 1. Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 2. Department of Medical Records, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 3. Department of Breast Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 4. Department of Obstetrics and Gynecology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 5. Department of Obstetrics and Gynecology, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 6. Department of Obstetrics and Gynecology, The Third Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
  • 7. Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China. Electronic address: [email protected].
  • 8. Medical Research Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Key Laboratory of Protein and Peptide Pharmaceuticals, CAS-University of Tokyo Joint Laboratory of Structural Virology and Immunology, Institute of Biophysics, Chinese Academy of Sciences, University of the Chinese Academy of Sciences, Beijing, China. Electronic address: [email protected].
PMID: 37211345 DOI: 10.1016/j.lfs.2023.121790
Abstract

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/SIRPα signal. In addition, compared to monotherapy, the concomitant administration of αCD47 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.

Keywords
CD47; HR-proficient; Olaparib; PARPi; TAMs.
Products