Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition

npj Precision Oncology

Article

Ying Ni¹  Hussein Al-Sudani²  Philip Jones³  Huseyin Karakilic³  Robert P. Edwards⁴  Haider Mahdi⁴  Alexander Olawaiye⁴  Peter G. Rose⁵  Lisa D. S. Johnson⁶  Gloria H. Y. Lin⁶  Robert A. Uger⁶  Lei Cui⁶ 

[1] Center for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland Clinic, 9500 Euclid Avenue, 44195, Cleveland, OH, USA;Internal Medicine Department, Einstein Medical Center Montgomery, Philadelphia, PA, USA;Magee Women’s Research Institute, University of Pittsburgh, 15213, Pittsburgh, PA, USA;Magee Women’s Research Institute, University of Pittsburgh, 15213, Pittsburgh, PA, USA;Magee Women’s Hospital, University of Pittsburgh Medical Center, 15213, Pittsburgh, PA, USA;Hillman Cancer Center, University of Pittsburgh, 15213, Pittsburgh, PA, USA;Section of Gynecologic Oncology, Women’s Health Institute, Cleveland Clinic, 9500 Euclid Avenue, Cleveland, OH, USA;Trillium Therapeutics Inc, 2488 Dunwin Dr., L5L 1J9, Mississauga, ON, Canada;

关键词: ;   

DOI  :  10.1038/s41698-023-00418-4

 received in 2022-11-22, accepted in 2023-06-20,  发布年份 2023

来源: Springer

【 摘 要 】

The objective was to correlate CD47 gene expression with resistance to immune checkpoint inhibitors (ICI) in tumor tissue of gynecological cancer (GC). Further, we sought to assess the efficacy of targeting CD47 pathway alone and in combination in pre-clinical ovarian cancer (OC) models. We performed transcriptomic analyses in GC treated with ICI. Signaling pathway enrichment analysis was performed using Ingenuity Pathway Analysis. Immune cell abundance was estimated. CD47 expression was correlated with other pathways, objective response, and progression-free survival (PFS). Anti-tumor efficacy of anti-CD47 therapy alone and in combination was investigated both in-vitro and in-vivo using cell-line derived xenograft (CDX) and patient-derived xenograft (PDX) models. High CD47 expression associated with lower response to ICI and trended toward lower PFS in GC patients. Higher CD47 associated negatively with PDL1 and CTLA4 expression, as well as cytotoxic T-cells and dendritic cells but positively with TGF-β, BRD4 and CXCR4/CXCL12 expression. Anti-CD47 significantly enhanced macrophage-mediated phagocytosis of OC cells in-vitro and exhibited potent anti-tumor activity in-vivo in OC CDX and PDX models. In-vitro treatment with PARPi increased CD47 expression. Anti-CD47 led to significantly enhanced in-vitro phagocytosis, enhanced STING pathway and synergized in-vivo when combined with PARP inhibitors in BRCA-deficient OC models. This study provides insight on the potential role of CD47 in mediating immunotherapy resistance and its association with higher TGF-β, BRD4 and CXCR4/CXCL12 expression. Anti-CD47 showed potent anti-tumor activity and synergized with PARPi in OC models. These data support clinical development of anti-CD47 therapy with PARPi in OC.

【 授权许可】

CC BY   
© The Author(s) 2023

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