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Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming.

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Mus musculus

PROVIDER: GSE235113 | GEO | 2024/06/04

REPOSITORIES: GEO

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Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming [dataset 1]

Project description:Innate immune checkpoint has emerging as a highly potential target for cancer immunotherapy in recent years. The CD47-SIRPα axis is the best-studied innate checkpoint in cancer. However, the transcription profile of tumor cell duiring CD47-SIRPα blockade therapy remains unclear.

2024-06-04 | GSE235111 | 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.

2024-06-04 | GSE235112 | GEO

Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming.

Project description:Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming.

| PRJNA984607 | ENA

Metabolic reprograming mediated by tumor cell-intrinsic type I IFN signaling is required for CD47-SIRPα blockade efficacy.

Project description:Type I interferons have been well recognized for their roles in various types of immune cells during tumor immunotherapy. However, their direct effects on tumor cells are less understood. Oxidative phosphorylation is typically latent in tumor cells. Whether oxidative phosphorylation can be targeted for immunotherapy remains unclear. Here, we find that tumor cell responsiveness to type I, but not type II interferons, is essential for CD47-SIRPα blockade immunotherapy in female mice. Mechanistically, type I interferons directly reprogram tumor cell metabolism by activating oxidative phosphorylation for ATP production in an ISG15-dependent manner. ATP extracellular release is also promoted by type I interferons due to enhanced secretory autophagy. Functionally, tumor cells with genetic deficiency in oxidative phosphorylation or autophagy are resistant to CD47-SIRPα blockade. ATP released upon CD47-SIRPα blockade is required for antitumor T cell response induction via P2X7 receptor-mediated dendritic cell activation. Based on this mechanism, combinations with inhibitors of ATP-degrading ectoenzymes, CD39 and CD73, are designed and show synergistic antitumor effects with CD47-SIRPα blockade. Together, these data reveal an important role of type I interferons on tumor cell metabolic reprograming for tumor immunotherapy and provide rational strategies harnessing this mechanism for enhanced efficacy of CD47-SIRPα blockade.

| S-EPMC11233683 | biostudies-literature

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

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

| PRJNA984609 | ENA

Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming [dataset 1]

Project description:Tumor cell intrinsic type I interferon signaling dictates CD47-SIRPα blockade immunotherapy via metabolic reprograming [dataset 1]

| PRJNA984610 | ENA

Insights into CD47/SIRPα axis-targeting tumor immunotherapy.

Project description:During the last decade, inhibitors targeting immune checkpoint programmed death ligand 1/PD-1 and cytotoxic T-lymphocyte-associated protein 4 have been one of the most significant advances for cancer therapy in clinic. However, most of these therapies focused on stimulating the adaptive immune system-mediated elimination of tumor. Recent studies indicated that CD47/Signal-regulatory protein alpha (SIRPα), an innate anti-phagocytic axis between cancer cells and macrophages, could be a promising therapeutic target. Here, we review the current knowledge about developing CD47/SIRPα checkpoint inhibitors, avoiding potential side effect and designing optimal combination therapies, and highlight the key points for future clinical applications of CD47/SIRPα axis-targeted tumor immunotherapy.

| S-EPMC8157794 | biostudies-literature

Blocking CD47-SIRPα Signal Axis as Promising Immunotherapy in Ovarian Cancer.

Project description:Among the three primary gynecological malignancies, ovarian cancer has the lowest incidence but the worst prognosis. Because of the poor prognosis of ovarian cancer patients treated with existing treatments, immunotherapy is emerging as a potentially ideal alternative to surgery, chemotherapy, and targeted therapy. Among immunotherapies, immune checkpoint inhibitors have been the most thoroughly studied, and many drugs have been successfully used in the clinic. CD47, a novel immune checkpoint, provides insights into ovarian cancer immunotherapy. This review highlights the mechanisms of tumor immune evasion via CD47-mediated inhibition of phagocytosis and provides a comprehensive insight into the progress of the relevant targeted agents in ovarian cancer.

| S-EPMC9969460 | biostudies-literature

CD47/SIRPα blocking peptide identification and synergistic effect with irradiation for cancer immunotherapy.

Project description:Immunotherapy has achieved remarkable advances via a variety of strategies against tumor cells that evade immune surveillance. As important innate immune cells, macrophages play important roles in maintaining homeostasis, preventing pathogen invasion, resisting tumor cells and promoting adaptive immune response. CD47 is found to be overexpressed on tumor cells and act as a don't eat me' signal, which contributes to immune evasion. Macrophages mediated phagocytosis via blockade CD47/SIRPα (signal regulatory protein alpha) interaction was proved to induce effective antitumor immune response. A novel peptide pep-20, specifically targeting CD47 and blocking CD47/SIRPα interaction, was identified via high-throughput phage display library bio-panning. The capability to enhance the macrophage-mediated phagocytosis activities and antitumor effects of pep-20 were investigated. The mechanism of pep-20 to induce T-cell response was explored by ex vivo analysis and confirmed via macrophage depleting strategy. The structure-activity relationship and D-amino acid substitution of pep-20 were also studied. The antitumor effects and mechanism of a proteolysis resistant D-amino acid derivate pep-20-D12 combined with irradiation (IR) were also investigated. Pep-20 showed remarkable enhancement of macrophage-mediated phagocytosis to both solid and hematologic tumor cells in vitro, and inhibited tumor growth in immune-competent tumor-bearing mice. Furthermore, pep-20 promoted macrophages to mobilize the antitumor T-cell response with minimal toxicity. Furthermore, systemic administration of the derivate pep-20-D12 showed robust synergistic antitumor efficacy in combination with IR. In summary, these results demonstrated that CD47/SIRPα blocking peptides, pep-20 and its derivate, could serve as promising candidates to promote macrophages-mediated phagocytosis and immune response in cancer immunotherapy.

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Cancer Therapy Targeting CD47/SIRPα.

Project description:In the past decade, the field of cancer immunotherapy has rapidly advanced, establishing a crucial role for immune checkpoint blockers in the treatment of a variety of cancer types. In parallel with these remarkable clinical developments, further efforts have focused on ways of unleashing adaptive immune responses against cancer. CD47, a cell surface molecule overexpressed by several cancer types that facilitates immune escape from macrophages, dendritic cells and natural killer cells, and its ligand SIRPα, have emerged as potential therapeutic targets. A number of agents directed to CD47/SIRPα have been developed and demonstrated preclinical activity. Early phase clinical trials are investigating CD47/SIRPα directed agents with available data, suggesting safety and preliminary activity. Herein, we provide an overview of the mechanistic rationale of targeting CD47/SIRPα axis and associated clinical evidence.

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