Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition
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...
| Main Authors: | , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2023-07-01
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| Series: | npj Precision Oncology |
| Online Access: | https://doi.org/10.1038/s41698-023-00418-4 |
| _version_ | 1797424702601297920 |
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| author | Hussein Al-Sudani 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 |
| author_facet | Hussein Al-Sudani 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 |
| author_sort | Hussein Al-Sudani |
| collection | DOAJ |
| description | 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. |
| first_indexed | 2024-03-09T08:05:48Z |
| format | Article |
| id | doaj.art-b9d424df472742e596767037c39f4aad |
| institution | Directory Open Access Journal |
| issn | 2397-768X |
| language | English |
| last_indexed | 2024-03-09T08:05:48Z |
| publishDate | 2023-07-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | npj Precision Oncology |
| spelling | doaj.art-b9d424df472742e596767037c39f4aad2023-12-03T00:20:23ZengNature Portfolionpj Precision Oncology2397-768X2023-07-017111010.1038/s41698-023-00418-4Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibitionHussein Al-Sudani0Ying Ni1Philip Jones2Huseyin Karakilic3Lei Cui4Lisa D. S. Johnson5Peter G. Rose6Alexander Olawaiye7Robert P. Edwards8Robert A. Uger9Gloria H. Y. Lin10Haider Mahdi11Internal Medicine Department, Einstein Medical Center MontgomeryCenter for Immunotherapy & Precision Immuno-Oncology, Lerner Research Institute, Cleveland ClinicMagee Women’s Research Institute, University of PittsburghMagee Women’s Research Institute, University of PittsburghTrillium Therapeutics IncTrillium Therapeutics IncSection of Gynecologic Oncology, Women’s Health Institute, Cleveland ClinicMagee Women’s Research Institute, University of PittsburghMagee Women’s Research Institute, University of PittsburghTrillium Therapeutics IncTrillium Therapeutics IncMagee Women’s Research Institute, University of PittsburghAbstract 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.https://doi.org/10.1038/s41698-023-00418-4 |
| spellingShingle | Hussein Al-Sudani 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 Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition npj Precision Oncology |
| title | Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition |
| title_full | Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition |
| title_fullStr | Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition |
| title_full_unstemmed | Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition |
| title_short | Targeting CD47-SIRPa axis shows potent preclinical anti-tumor activity as monotherapy and synergizes with PARP inhibition |
| title_sort | targeting cd47 sirpa axis shows potent preclinical anti tumor activity as monotherapy and synergizes with parp inhibition |
| url | https://doi.org/10.1038/s41698-023-00418-4 |
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