Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy

Yanagita, Tadahiko; Murata, Yoji; Tanaka, Daisuke; Motegi, Sei‐ichiro; Arai, Eri; Daniwijaya, Edwin Widyanto; Hazama, Daisuke; Washio, Ken; Saito, Yasuyuki; Kotani, Takenori; Ohnishi, Hiroshi; Oldenborg, Per Arne; García, Noel Verján; Miyasaka, Masayuki; Ishikawa, Osamu; Kanai, Yae; Komori, Takahide; Matozaki, Takashi

doi:10.1172/jci.insight.89140

Cited by 121 publications

(163 citation statements)

References 60 publications

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“…Blocking Abs to SIRPα might also have therapeutic effects as single agents in the case of SIRPα‐expressing tumors, with the antitumor effects of such Abs being mediated by a dual mechanism of action: direct induction of ADCP of tumor cells by macrophages and blockade of CD47‐SIRPα signaling that negatively regulates such phagocytosis (Figure B). Similar to the increased expression of CD47 apparent in many types of cancer, SIRPα is also more prominently expressed in tumor tissue from patients with renal cell carcinoma or melanoma compared with the surrounding normal tissue . Of note, treatment with a blocking Ab to mouse SIRPα resulted in a marked reduction in the tumor burden of immunocompetent mice injected with syngeneic renal cell carcinoma or melanoma cells, both of which highly expressed endogenous SIRPα .…”

Section: Blockade Of the Cd47‐sirpα Signaling System Has Antitumor Efmentioning

confidence: 68%

“…Similar to the increased expression of CD47 apparent in many types of cancer, SIRPα is also more prominently expressed in tumor tissue from patients with renal cell carcinoma or melanoma compared with the surrounding normal tissue . Of note, treatment with a blocking Ab to mouse SIRPα resulted in a marked reduction in the tumor burden of immunocompetent mice injected with syngeneic renal cell carcinoma or melanoma cells, both of which highly expressed endogenous SIRPα . This antitumor action of the Ab was significantly attenuated by selective depletion of macrophages.…”

Section: Blockade Of the Cd47‐sirpα Signaling System Has Antitumor Efmentioning

confidence: 68%

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CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

et al. 2018

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Tumor cells evade immune surveillance through direct or indirect interactions with various types of immune cell, with much recent attention being focused on modifying immune cell responses as the basis for the development of new cancer treatments. Signal regulatory protein α (SIRPα) and CD47 are both transmembrane proteins that interact with each other and constitute a cell‐cell communication system. SIRPα is particularly abundant in myeloid cells such as macrophages and dendritic cells, whereas CD47 is expressed ubiquitously and its expression level is elevated in cancer cells. Recent studies have shown that blockade of CD47‐SIRPα interaction enhances the phagocytic activity of phagocytes such as macrophages toward tumor cells in vitro as well as resulting in the efficient eradication of tumor cells in a variety of xenograft or syngeneic mouse models of cancer. Moreover, CD47 blockade has been shown to promote the stimulation of tumor‐specific cytotoxic T cells by macrophages or dendritic cells. Biological agents, such as Abs and recombinant proteins, that target human CD47 or SIRPα have been developed and are being tested in preclinical models of human cancer or in clinical trials with cancer patients. Preclinical studies have also suggested that CD47 or SIRPα blockade may have a synergistic antitumor effect in combination with immune checkpoint inhibitors that target the adaptive immune system. Targeting of the CD47‐SIRPα signaling system is thus a promising strategy for cancer treatment based on modulation of both innate and acquired immune responses to tumor cells.

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Section: Blockade Of the Cd47‐sirpα Signaling System Has Antitumor Efmentioning

confidence: 68%

Section: Blockade Of the Cd47‐sirpα Signaling System Has Antitumor Efmentioning

confidence: 68%

CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

et al. 2018

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“…Phase I clinical trials involving single agent administration of monoclonal antibodies blocking the CD47‐SIRPα include humanized CD47‐blocking agents such as Hu5F9‐G4, CC‐90002, and SIRPα protein variants such as TTI‐621 and ALX148 . Clinical trial evidence increasingly points to limited anticancer efficacies associated with these therapies owing to limitations such as subpar binding affinities of SIRPα antibodies and systemic toxicities involving anti‐CD47‐based therapies …”

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confidence: 99%

CSF1R‐ and SHP2‐Inhibitor‐Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor‐Associated Macrophages

et al. 2019

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Immune modulation of macrophages has emerged as an attractive approach for anti‐cancer therapy. However, there are two main challenges in successfully utilizing macrophages for immunotherapy. First, macrophage colony stimulating factor (MCSF) secreted by cancer cells binds to colony stimulating factor 1 receptor (CSF1‐R) on macrophages and in turn activates the downstream signaling pathway responsible for polarization of tumor‐associated macrophages (TAMs) to immunosuppressive M2 phenotype. Second, ligation of signal regulatory protein α (SIRPα) expressed on myeloid cells to CD47, a transmembrane protein overexpressed on cancer cells, activates the Src homology region 2 (SH2) domain ‐phosphatases SHP‐1 and SHP‐2 in macrophages. This results in activation of “eat‐me‐not” signaling pathway and inhibition of phagocytosis. Here, it is reported that self‐assembled dual‐inhibitor‐loaded nanoparticles (DNTs) target M2 macrophages and simultaneously inhibit CSF1R and SHP2 pathways. This results in efficient repolarization of M2 macrophages to an active M1 phenotype, and superior phagocytic capabilities as compared to individual drug treatments. Furthermore, suboptimal dose administration of DNTs in highly aggressive breast cancer and melanoma mouse models show enhanced anti‐tumor efficacy without any toxicity. These studies demonstrate that the concurrent inhibition of CSF1‐R and SHP2 signaling pathways for macrophage activation and phagocytosis enhancement could be an effective strategy for macrophage‐based immunotherapy.

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“…The expression of SIRP‐α on macrophages prevents phagocytosis of Ig‐opsonized red blood cells through the interaction with CD47; whereas depletion of SIRP‐α promotes the FcR‐mediated phagocytosis of red blood cells . Yanagita et al found that blockage of the interaction between SIRP‐α and CD47 remarkably suppressed tumor formation through the enhancement of the cellular phagocytosis of tumor cells by macrophages . In this study, we found that the SIRP expression in peritoneal macrophages from women with EM was significantly higher than the expression observed in control subjects.…”

Section: Discussionmentioning

confidence: 47%

Eutopic endometrium from patients with endometriosis modulates the expression of CD36 and SIRP‐α in peritoneal macrophages

Xie

et al. 2019

J of Obstet and Gynaecol

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Aim This study aimed to investigate the in vitro alterations of the expression of signal regulatory protein‐α (SIRP‐α) and CD36 in macrophages in the endometriosis condition. Methods The expression of SIRP‐α and CD36 was measured in peritoneal macrophages and peripheral blood mononuclear cells of endometriosis patients and control participants. The expressions of SIRP‐α and CD36 were measured in human acute monocytic leukemia (THP‐1) cell‐derived macrophages that were treated with interleukin‐6 (IL‐6)‐induced conditioned medium, eutopic versus normal endometrial homogenate, or lipopolysaccharide in the presence or absence of nuclear factor kappa‐B (NF‐κB) or transforming growth factor (TGF‐β) inhibitors, respectively. Results Peritoneal macrophages that were isolated from women with endometriosis exhibited an enhanced expression of SIRP‐α and a decreased expression of CD36 compared to control participants. Women with endometriosis had significantly higher levels of SIRP‐α and CD36 in peripheral circulating mononuclear cells than in control participants. SIRP‐α expression was significantly increased, whereas the CD36 expression was decreased in THP‐1 cell‐derived macrophages after treatment with eutopic endometrial homogenate. Intervention with IL‐6‐induced conditioned medium resulted in the downregulation of SIRP‐α but the upregulation of CD36 in THP‐1 cells. Incubation with the NF‐κBp50 inhibitor decreased the expression of CD36 and SIRP‐α in macrophages that were treated with normal endometrial homogenate, whereas the TGF‐β inhibitor enhanced the CD36 expression of THP‐1 cell‐derived macrophages treated with eutopic endometrial homogenate. Conclusion The eutopic endometrium could reduce the phagocytic ability of peritoneal macrophages in women with endometriosis through the modulation of SIRP‐α and CD36 expression. Inhibition of the TGF‐β signal pathway may be a potential therapeutic target for the treatment of endometriosis.

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Anti-SIRPα antibodies as a potential new tool for cancer immunotherapy

Cited by 121 publications

References 60 publications

CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

CD47‐signal regulatory protein α signaling system and its application to cancer immunotherapy

CSF1R‐ and SHP2‐Inhibitor‐Loaded Nanoparticles Enhance Cytotoxic Activity and Phagocytosis in Tumor‐Associated Macrophages

Eutopic endometrium from patients with endometriosis modulates the expression of CD36 and SIRP‐α in peritoneal macrophages

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