Targeting CD47-SIRPa Axis Shows Potent Preclinical Anti-Tumor Activity as Monotherapy and Synergizes with PARP Inhibition

Authors

Hussein Al-Sudani, Jefferson Einstein Montgomery Hospital
Ying Ni
Philip Jones
Huseyin Karakilic
Lei Cui
Lisa D.S. Johnson
Peter G. Rose
Alexander Olawaiye
Robert P. Edwards
Robert A. Uger
Gloria H.Y. Lin
Haider Mahdi

Document Type

Article

Publication Date

7-19-2023

Comments

This article is the author’s final published version in npj Precision Oncology, Volume 7, July 2023, Article number 69.

The published version is available at https://doi.org/10.1038/s41698-023-00418-4. © 2023. The Author(s).

Abstract

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.

Recommended Citation

Al-Sudani, Hussein; Ni, Ying; Jones, Philip; Karakilic, Huseyin; Cui, Lei; Johnson, Lisa D.S.; Rose, Peter G.; Olawaiye, Alexander; Edwards, Robert P.; Uger, Robert A.; Lin, Gloria H.Y.; and Mahdi, Haider, "Targeting CD47-SIRPa Axis Shows Potent Preclinical Anti-Tumor Activity as Monotherapy and Synergizes with PARP Inhibition" (2023). Einstein Health Papers. Paper 16.
https://jdc.jefferson.edu/einsteinfp/16

Creative Commons License

This work is licensed under a Creative Commons Attribution 4.0 License.

Language

English