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Targeted release of a bispecific fusion protein SIRPα/Siglec-10 by oncolytic adenovirus reinvigorates tumor associated macrophages to improve therapeutic outcomes in solid tumors

ABSTRACT: CD47/SIRPα and CD24/Siglec-10 signaling pathways have been found to suppress macrophage phagocytosis of malignant cells. We constructed a recombinant oncolytic adenovirus expressing a fusion protein composed of the extracellular domains of murine SIRPα and Siglec-10 (SIRPα/Siglec-10), termed AdV-mSS. Intratumoral administration of AdV-SS markedly enhanced antitumor efficacy than AdV-Ctrl in multiple solid tumor models. To reveal differences in biological processes between them. subcutaneous 14-day H22-CAR -bearing BALB/c mice were intratumorally injected with PBS, 5 × 10^8 IFU AdV-Ctrl, or 5 × 10^8 IFU AdV-mSS twice. Forty-eight hours post-treatment, we harvested tumor tissue and sorted these TAMs by anti-mouse F4/80 magnetic beads. Samples were subjected to transcriptome sequencing.

ORGANISM(S): Mus musculus

PROVIDER: GSE275905 | GEO | 2025/04/09

REPOSITORIES: GEO

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Tumor-intrinsic expression of signal regulatory protein α (SIRPα) contributes to the suppression of anti-tumor immune responses [RNA_CD172KO]

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2026-04-27 | GSE319206 | GEO

Targeted release of a bispecific fusion protein SIRPα/Siglec-10 by oncolytic adenovirus reinvigorates tumor associated macrophages to improve therapeutic outcomes in solid tumors

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Project description:T-cell immune checkpoint inhibitors have revolutionized cancer immunotherapy. In addition to T cells, immune checkpoint molecules have also been described for myeloid cells, with CD47 on tumor cells and Signal Regulatory Protein α (SIRPα) on effector cells being the most established example (Maute et al. Immunooncol Technol. 2022). Blockade of this checkpoint by CD47 or SIRPα targeting molecules has been demonstrated to enhance the efficacy of therapeutic antibodies in many preclinical tumor models (Müller et al. Blood. 2022, Schewe et al. Hemasphere. 2024). Next to CD47/SIRPα blocking molecules, inhibition of Glutaminyl-Peptide Cyclotransferase-Like (QPCTL) - the enzyme that catalyzes functionally relevant pyroglutamate (pGlu) formation on many peptides and proteins including CD47 - was shown to modify the myeloid tumor cell infiltrate (Barreira et al. Nat Immunol. 2022) and to improve antibody-dependent cellular phagocytosis (ADCP) and antibody-dependent cellular cytotoxicity (ADCC) against tumor cells (Logtenberg et al. Nat Med. 2019, Wu et al. Cell Res. 2019, Baumann et al. Front Immunol. 2021). Crystallographic analyses of CD47 in complex with SIRPα revealed that the CD47 binding pocket for SIRPα contains pGlu at the N-terminus (Hatherley et al. Mol Cell. 2008). However, on cellular level the direct involvement of pGlu in the CD47/SIRPα interaction has not been confirmed yet. We generated human CD47 Fc proteins, that contain either a native CD47 ectodomain with N-terminal pGlu (CD47-wt) or a mutated version with alanine at the N-terminus (CD47-Q1A), which was confirmed by mass spectrometry. Differential binding of CD47-wt and CD47-Q1A revealed that pGlu on CD47 is essential for binding to SIRPα on macrophages, supporting that inhibition of QPCTL is a good therapeutic option for enhanced tumor cell killing through CD47/SIRPα interference.

2026-05-19 | PXD066444 | Pride

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2024-08-10 | GSE264061 | GEO

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Project description:Therapies targeting the CD47–SIRPα "don't eat me" axis are currently hampered by limited tissue penetration and dose-limiting hematotoxicity. Here, we report a tumor-targeted mRNA nanotherapeutic that selectively degrades SIRPα on macrophages to unleash antitumor immunity in colorectal cancer. We formulated mRNA encoding an Fc-fused SIRPα degrader into VEGFR2-targeted lipid nanoparticles (LNPs) to achieve tumor-specific delivery. This system triggers lysosomal degradation of SIRPα, repolarizing tumor-associated macrophages toward a pro-inflammatory, phagocytic state that drives CD8⁺ T cell priming. In contrast to the hematologic toxicity associated with systemic CD47 blockade, this strategy demonstrated superior tumor control in syngeneic and orthotopic CRC models while preserving a normal hematologic profile. Single-cell transcriptomics confirmed the remodeling of the immunosuppressive myeloid landscape. These findings establish targeted SIRPα degradation as a potent, safe alternative to systemic CD47 blockade, offering a versatile platform to reprogram myeloid checkpoints in solid tumors.

2026-05-26 | GSE331406 | GEO

Transcript profiling of WT and SIRPα KO BMDMs post-M1 activation in the presence of mCD47.ex

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2021-03-19 | GSE169177 | GEO

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Project description:We found that overexpression of APOA1 in glioblastoma (GBM) promotes cholesterol efflux from TAMs and restores phagocytosis and antigen presentation. Therefore, we constructed a recombinant oncolytic adenovirus expressing APOA1 to carry the cholesterol regulatory elements of TAMs. AdV-APOA1 exhibited better antitumor effects than AdV-Ctrl in several orthotopic GBM tumor models. Further, we collected virus-treated GL261-CAR tumors for RNA-seq to reveal differences in biological processes between them. Specifically, intracranial 14-day GL261-CAR-bearing C57BL/6J mice were i.t. injected with 1 × 108 PFU AdV-Ctrl or 1 × 108 PFU AdV-APOA1. The tumor bulks were then collected to perform transcriptome RNA-seq analysis 3 days after virus injection.

2022-05-04 | GSE201976 | GEO

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2024-06-04 | GSE235111 | GEO

CD47-SIRPα axis blockade in NASH promotes necroptotic hepatocyte clearance by liver macrophages and decreases hepatic fibrosis

Project description:Necroptosis contributes to hepatocyte death (HC) in non-alcoholic steatohepatitis (NASH), but the fate and roles of necroptotic hepatocytes (necHCs) in NASH remain unknown. We show here that the accumulation of necHCs is associated with worsening NASH in humans and in mice with diet-induced NASH and that NASH liver showed evidence of impaired necHC clearance by liver macrophages. Further, the "don't-eat-me" ligand CD47 on HCs and its receptor, SIRPα, on liver macrophages, were markedly upregulated in human and mouse NASH. In vitro, anti-CD47 or anti-SIRPα promoted necHC engulfment by primary liver macrophages. In a proof-of-concept mouse model of inducible HC necroptosis, anti-CD47 increased necHC uptake by liver macrophages and inhibited hepatic stellate cell (HSC) activation, which is responsible for liver fibrogenesis. Most importantly, treatment of two mouse models of diet-induced NASH with anti-CD47 or anti-SIRPα increased the uptake of necHC by liver macrophages and decreased HSC activation and liver fibrosis. These findings provide evidence that impaired clearance of necHCs by liver macrophages due to CD47-SIRPα upregulation contributes to fibrotic NASH and suggest therapeutic blockade of the CD47-SIRPα axis as a strategy to decrease the accumulation of necHCs in NASH liver and dampen the progression of hepatic fibrosis.

2022-11-25 | GSE197111 | GEO

Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming [dataset 2]

Project description:Type I interferons (IFN-Is) have been well recognized for their roles in immune cells in tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation (OXPHOS) is typically latent in tumor cells. However, whether OXPHOS can be targeted for immunotherapy remains unclear. Here, we found that tumor cell responsiveness to IFN-Is is essential for CD47-SIRPα blockade immunotherapy. Interestingly, IFN-Is directly reprogram tumor cell metabolism by activating OXPHOS for ATP production via ISG15. ATP extracellular release is also enhanced by IFN-Is via autophagy. Tumor cells with a genetic deficiency in OXPHOS or autophagy were resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade primes the anti-tumor T cell response via ATP-P2X7 receptor-mediated dendritic cell activation. Further combination with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, showed synergistic anti-tumor effects. Together, these data reveal the unrecognized mechanisms of IFN-Is on tumor cell metabolic reprograming in tumor immunotherapy and provide novel strategies harnessing this pathway for enhanced efficacy of CD47-SIRPα blockade.

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