Targeted inhibition of CD47-SIRPα requires Fc-FcγR interactions to maximize activity in T-cell lymphomas

Jain, Salvia; Scoyk, Alexandria Van; Morgan, Elizabeth A.; Matthews, Andrew; Stevenson, Kristen E.; Newton, Gail; Powers, Foster; Autio, Anu; Louissaint, Abner; Pontini, Guillemette; Aster, Jon C.; Luscinskas, Francis W.; Weinstock, David M.

doi:10.1182/blood.2019001744

Cited by 50 publications

(48 citation statements)

References 31 publications

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“…While macrophages are the main effector cells of CD47/ SIRPα pathway from current studies, it is undeniable that the presence of Fc receptor (FcR)-mediated ADCC and antibody-dependent cellular phagocytosis (ADCP) effectively synergize antitumor therapy by phagocytes, even the contradictory relationship between antitumor effects and potential side effects can be balanced. 39 Therefore, agents of CD47/SIRPα blockade for enhancement of Figure 6 Combination of pep-20-D12 treatment with IR synergistically delays tumor growth. C57BL/6 mice were transplanted with 1×10 6 MC38 cells on the right flank, and tumors were allowed to grow to ~100 mm 3 Open access phagocytosis function by blocking 'don't eat me' signals combined with cancer-targeting therapeutic antibodies, FcR-mediated ADCC and ADCP, may be a more effective approach to potently eliminate tumors at the current stage.…”

Section: Open Accessmentioning

confidence: 99%

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

Wang¹,

Sun²,

Zhou³

et al. 2020

J Immunother Cancer

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BackgroundImmunotherapy 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.MethodsA 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.ResultsPep-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.ConclusionIn 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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Section: Open Accessmentioning

confidence: 99%

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

Wang¹,

Sun²,

Zhou³

et al. 2020

J Immunother Cancer

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“…Therefore, blocking CD47-SIRPα checkpoint has been applied for immunotherapy. Inhibition of CD47 binding to SIRPα activates both innate and adaptive immunity by promoting presentation of tumor antigens to CD8 T lymphocytes, resulting in cancer cell destruction by macrophage and anti-tumor cytotoxicity due to antigen-presentation by dendritic cells, respectively [11,12]. There are several CD47 antagonists have shown strong e cacy against solid and hematological tumors undergoing clinical trials, such as Hu5F9 and TTI-621 [9,12].…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of CD47 binding to SIRPα activates both innate and adaptive immunity by promoting presentation of tumor antigens to CD8 T lymphocytes, resulting in cancer cell destruction by macrophage and anti-tumor cytotoxicity due to antigen-presentation by dendritic cells, respectively [11,12]. There are several CD47 antagonists have shown strong e cacy against solid and hematological tumors undergoing clinical trials, such as Hu5F9 and TTI-621 [9,12]. Hu5F9 is a humanized monoclonal antibody binding to CD47 with high a nity and has been proposed to activate a pro-phagocytic signal pathway to eliminate the tumor cells [13].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effects of Circulating Natural Autoantibodies to CD47-derived Peptides on Oral Squamous Cell Carcinoma Cells

Liu

Meng

et al. 2020

Preprint

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Background Natural autoantibodies serve as an important anti-tumorigenic system due to its immune surveillance function. The present study aims to investigate whether circulating natural IgG autoantibodies against cluster of differentiation 47 (CD47) could inhibit the proliferation of oral squamous cell carcinoma (OSCC) cells. Methods The expression of 14 tumor-targeted genes in three OSCC cell lines was analyzed with quantitative real-time PCR. The in-house enzyme-linked immunosorbent assay (ELISA) was then performed to detect plasma IgG antibodies against CD47. Three OSCC cell lines were treated with 20% human plasma positive and negative for anti-CD47 IgG, respectively, followed by analysis of cell proliferation, apoptosis and invasion/metastasis. Results CD 47 showed highest expression among all 14 genes detected in three OSCC cell lines. Plasma anti-CD47 IgG significantly inhibited the viability of all three OSCC cell lines. The proportions of apoptotic cells were remarkably higher in OSCC cells treated with anti-CD47 IgG-positive plasma than those treated with IgG-negative plasma. Furthermore, the cell invasion/metastasis was attenuated evidently with the attribution of plasma anti-CD47 IgG. Conclusions Natural autoantibodies against CD47 may be a potential target for OSCC immunotherapy.

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“…Therefore, blocking CD47-SIRPα checkpoint has been applied for immunotherapy. Inhibition of CD47 binding to SIRPα activates both innate and adaptive immunity by promoting presentation of tumor antigens to CD8 T lymphocytes, resulting in cancer cell destruction by macrophage and anti-tumor cytotoxicity due to antigenpresentation by dendritic cells, respectively [11,12]. There are several CD47 antagonists have shown strong e cacy against solid and hematological tumors undergoing clinical trials, such as Hu5F9 and TTI-621 [9,12].…”

Section: Introductionmentioning

confidence: 99%

“…Inhibition of CD47 binding to SIRPα activates both innate and adaptive immunity by promoting presentation of tumor antigens to CD8 T lymphocytes, resulting in cancer cell destruction by macrophage and anti-tumor cytotoxicity due to antigenpresentation by dendritic cells, respectively [11,12]. There are several CD47 antagonists have shown strong e cacy against solid and hematological tumors undergoing clinical trials, such as Hu5F9 and TTI-621 [9,12]. Hu5F9 is a humanized monoclonal antibody binding to CD47 with high a nity and has been proposed to activate a pro-phagocytic signal pathway to eliminate the tumor cells [13].…”

Section: Introductionmentioning

confidence: 99%

Inhibitory Effects of Circulating Natural Autoantibodies to CD47-derived Peptides on Oral Squamous Cell Carcinoma Cells

Liu¹,

Meng²,

He³

et al. 2020

Preprint

View full text Add to dashboard Cite

Natural autoantibodies serve as an important anti-tumorigenic system due to its immune surveillance function. The present study aims to investigate whether circulating natural IgG autoantibodies against cluster of differentiation 47 (CD47) could suppress the proliferation of oral squamous cell carcinoma (OSCC) cells. Three OSCC cell lines were used for this study. The expression of fourteen tumor related genes including CD47 were tested. OSCC cells were grown, respectively, with 20% human plasma positive and negative for anti-CD47 IgG. Cell proliferation, apoptosis and invasion/metastasis were examined. The results showed that CD47 presented highest expression among all 14 genes detected in OSCC cells. Plasma anti-CD47 IgG significantly inhibited the viability of all three OSCC cell lines. The proportions of apoptotic cells were remarkably higher in OSCC cells treated with anti-CD47 IgG-positive plasma than those treated with IgG-negative plasma. Furthermore, the cell invasion/metastasis was attenuated evidently with the attribution of plasma anti-CD47 IgG. In conclusion, natural autoantibodies against CD47 may be a potential target for OSCC immunotherapy.

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Targeted inhibition of CD47-SIRPα requires Fc-FcγR interactions to maximize activity in T-cell lymphomas

Abstract: This study reveals that successful therapeutic targeting of the CD47-SIRPα axis in peripheral T-cell lymphoma is highly dependent on the Fc-FcγR interaction and is augmented by cotreatment with the anti-CCR4–targeted monoclonal antibody mogamulizumab.

Cited by 50 publications

References 31 publications

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

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

Inhibitory Effects of Circulating Natural Autoantibodies to CD47-derived Peptides on Oral Squamous Cell Carcinoma Cells

Inhibitory Effects of Circulating Natural Autoantibodies to CD47-derived Peptides on Oral Squamous Cell Carcinoma Cells

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