2. Academic Validation
  3. 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.
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.

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