1. Academic Validation
  2. PARP inhibition synergizes with CD47 blockade to promote phagocytosis by tumor-associated macrophages in homologous recombination-proficient tumors

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

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: fccshengyq@zzu.edu.cn.
  • 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: zhihai@ibp.ac.cn.
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.

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