The SIRPα–CD47 immune checkpoint in NK cells

Deuse, T.; Hu, Xiaomeng; Agbor‐Enoh, Sean; Jang, Moon Kyoo; Alawi, Malik; Saygı, Ceren; Gravina, Alessia; Tediashvili, Grigol; Nguyen, Vinh; Liu, Yuan; Valantine, Hannah A.; Lanier, Lewis L.; Schrepfer, Sonja

doi:10.1084/jem.20200839

Cited by 107 publications

(108 citation statements)

References 45 publications

(64 reference statements)

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“…In any stage of HER2 + breast cancer, it may be beneficial to add CD47 blockade to anti-HER2 therapy to enhance the innate antitumor immune response. Recently published data from Deuse et al (54) demonstrate that NK cells with up-regulated SIRPα can also be inhibited by CD47 on the surface of their target cells, further strengthening the likelihood that adding CD47 blockade can benefit patients undergoing anti-HER2 therapy, either after a relapse or as a front-line therapy. That possibility will need to be examined in the future to determine the magnitude of NK, macrophage, and if antigen cross-presentation occurs, adaptive immune T cells, as well as de novo endogenous polyclonal antibody responses to tumor cells.…”

Section: Discussionmentioning

confidence: 94%

Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance

Upton

Banuelos

Feng

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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Trastuzumab, a targeted anti-human epidermal-growth-factor receptor-2 (HER2) monoclonal antibody, represents a mainstay in the treatment of HER2-positive (HER2+) breast cancer. Although trastuzumab treatment is highly efficacious for early-stage HER2+ breast cancer, the majority of advanced-stage HER2+ breast cancer patients who initially respond to trastuzumab acquire resistance to treatment and relapse, despite persistence of HER2 gene amplification/overexpression. Here, we sought to leverage HER2 overexpression to engage antibody-dependent cellular phagocytosis (ADCP) through a combination of trastuzumab and anti-CD47 macrophage checkpoint immunotherapy. We have previously shown that blockade of CD47, a surface protein expressed by many malignancies (including HER2+ breast cancer), is an effective anticancer therapy. CD47 functions as a “don’t eat me” signal through its interaction with signal regulatory protein-α (SIRPα) on macrophages to inhibit phagocytosis. Hu5F9-G4 (magrolimab), a humanized monoclonal antibody against CD47, blocks CD47’s “don’t eat me” signal, thereby facilitating macrophage-mediated phagocytosis. Preclinical studies have shown that combining Hu5F9-G4 with tumor-targeting antibodies, such as rituximab, further enhances Hu5F9-G4’s anticancer effects via ADCP. Clinical trials have additionally demonstrated that Hu5F9-G4, in combination with rituximab, produced objective responses in patients whose diffuse large B cell lymphomas had developed resistance to rituximab and chemotherapy. These studies led us to hypothesize that combining Hu5F9-G4 with trastuzumab would produce an anticancer effect in antibody-dependent cellular cytotoxicity (ADCC)-tolerant HER2+ breast cancer. This combination significantly suppressed the growth of ADCC-tolerant HER2+ breast cancers via Fc-dependent ADCP. Our study demonstrates that combining trastuzumab and Hu5F9-G4 represents a potential new treatment option for HER2+ breast cancer patients, even for patients whose tumors have progressed after trastuzumab.

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Section: Discussionmentioning

confidence: 94%

Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance

Upton

Banuelos

Feng

et al. 2021

Proc. Natl. Acad. Sci. U.S.A.

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“…Outside of microglia, SIRPα in the eye is normally expressed in the synapse-rich plexiform layers of the retina ( 22 ). However, the protein is also present on multiple immune cell populations, including monocytes, macrophages, neutrophils, and dendritic cells, and has more recently been described on natural killer cells and a subset of cytotoxic T cells ( 29 , 32 , 33 ). Binding of CD47 to SIRPα on immune cell populations consistently acts as a negative checkpoint, whether by inhibiting phagocytosis, preventing cell killing, or impeding recruitment of adaptive immunity ( 29 ).…”

Section: Discussionmentioning

confidence: 99%

Augmentation of CD47/SIRPα signaling protects cones in genetic models of retinal degeneration

Wang¹,

Xue²,

Cepko³

2021

JCI Insight

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Inherited retinal diseases such as retinitis pigmentosa (RP) can be caused by thousands of different mutations, a small number of which have been successfully treated with gene replacement. However, this approach has yet to scale and may not be feasible in many cases, highlighting the need for interventions that could benefit more patients. Here, we found that microglial phagocytosis is upregulated during cone degeneration in RP, suggesting that expression of "don't eat me" signals such as CD47 might confer protection to cones. To test this, we delivered an adeno-associated viral (AAV) vector expressing CD47 on cones, which promoted cone survival in three mouse models of RP and preserved visual function. Cone rescue with CD47 required a known interacting protein, signal regulatory protein alpha (SIRPα), but not an alternative interacting protein, thrombospondin-1 (TSP1). Despite the correlation between increased microglial phagocytosis and cone death, microglia were dispensable for the prosurvival activity of CD47, suggesting that CD47 interacts with SIRPα on non-microglial cells to alleviate degeneration. These findings establish augmentation of CD47-SIRPα signaling as a potential treatment strategy for RP and possibly other forms of neurodegeneration.

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“…The benefit of activating macrophages in AML has been demonstrated by the αCD47 antibody magrolimab in combination with azacytidine [ 8 ]. Recent data additionally suggest that upon activation, NK cells can upregulate SIRPα, which leads to strong inhibition of cytotoxicity when interacting with CD47 on the surface of target cells [ 72 ]. An effective blockade of CD47 signalling could therefore be the reason we observed an extremely potent upregulation of CD69 on NK cells in response to 2 × SIRPα-αCD123 treatment.…”

Section: Discussionmentioning

confidence: 99%

SIRPα-αCD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells

et al. 2021

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Background Acute myeloid leukaemia (AML) stem cells (LSCs) cause disease relapse. The CD47 “don’t eat me signal” is upregulated on LSCs and contributes to immune evasion by inhibiting phagocytosis through interacting with myeloid-specific signal regulatory protein alpha (SIRPα). Activation of macrophages by blocking CD47 has been successful, but the ubiquitous expression of CD47 on healthy cells poses potential limitations for such therapies. In contrast, CD123 is a well-known LSC-specific surface marker utilized as a therapeutic target. Here, we report the development of SIRPα-αCD123 fusion antibodies that localize the disruption of CD47/SIRPα signalling to AML while specifically enhancing LSC clearance. Methods SIRPα-αCD123 antibodies were generated by fusing the extracellular domain of SIRPα to an αCD123 antibody. The binding properties of the antibodies were analysed by flow cytometry and surface plasmon resonance. The functional characteristics of the fusion antibodies were determined by antibody-dependent cellular phagocytosis and antibody-dependent cellular cytotoxicity assays using primary AML patient cells. Finally, an in vivo engraftment assay was utilized to assess LSC targeting. Results SIRPα-αCD123 fusion antibodies exhibited increased binding and preferential targeting of CD123+ CD47+ AML cells even in the presence of CD47+ healthy cells. Furthermore, SIRPα-αCD123 fusion antibodies confined disruption of the CD47-SIRPα axis locally to AML cells. In vitro experiments demonstrated that SIRPα-αCD123 antibodies greatly enhanced AML cell phagocytosis mediated by allogeneic and autologous macrophages. Moreover, SIRPα-αCD123 fusion antibodies efficiently targeted LSCs with in vivo engraftment potential. Conclusions SIRPα-αCD123 antibodies combine local CD47 blockade with specific LSC targeting in a single molecule, minimize the risk of targeting healthy cells and efficiently eliminate AML LSCs. These results validate SIRPα-αCD123 antibodies as promising therapeutic interventions for AML.

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The SIRPα–CD47 immune checkpoint in NK cells

Cited by 107 publications

References 45 publications

Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance

Combining CD47 blockade with trastuzumab eliminates HER2-positive breast cancer cells and overcomes trastuzumab tolerance

Augmentation of CD47/SIRPα signaling protects cones in genetic models of retinal degeneration

SIRPα-αCD123 fusion antibodies targeting CD123 in conjunction with CD47 blockade enhance the clearance of AML-initiating cells

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