CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer

Weiskopf, Kipp; Jahchan, Nadine S.; Schnorr, Peter J.; Cristea, Sandra; Ring, Aaron M.; Maute, Roy L.; Volkmer, Anne Kathrin; Volkmer, Jens Peter; Liu, Jie; Lim, Jing Shan; Yang, Dian; Seitz, Garrett; Nguyen, Thuyen; Wu, Di; Jude, Kevin; Guerston, Heather; Barkal, Amira; Trapani, Francesca; George, Julie; Poirier, John T.; Gardner, Eric E.; Miles, Linde A.; Stanchina, Elisa de; Lofgren, Shane; Vogel, Hannes; Winslow, Monte M.; Dive, Caroline; Thomas, Roman K.; Rudin, Charles M.; Rijn, Matt van de; Majeti, Ravindra; García, K. Christopher; Weissman, Irving L.; Sage, Julien

doi:10.1172/jci81603

Cited by 353 publications

(280 citation statements)

References 55 publications

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“…It has been demonstrated that blocking CD47-SIRPα signaling with anti-CD47 antibodies enhances phagocytic activity from M1 and M2 macrophages and promotes tumor regression (37). Furthermore, blocking CD47-SIRPα signaling enhances the macrophage phagocytosis of various tumor cells in vitro (18,22,38). In the present study, it was demonstrated that human M2 macrophages phagocytized CD47-high ESCC cells in a dose-dependent manner following the addition of anti-CD47 antibodies to the cell culture.…”

Section: Discussionsupporting

confidence: 49%

Characterization of cluster of differentiationï¿½47 expression and its potential as a therapeutic target in esophageal squamous cell cancer

Zhao

Wang

et al. 2017

Oncol Lett

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Abstract. The increased expression of cluster of differentiation (CD)47 has been identified in a number of different tumor types and is recognized as an adverse prognostic factor that indicates an increased risk of mortality in patients. The binding of CD47 to signal regulatory protein α (SIRPα) inhibits the macrophage phagocytosis of tumor cells by triggering an inhibitory 'do not eat me' signal. This is one of the mechanisms used by tumor cells to evade immune surveillance. In the present study, CD47 levels and macrophage infiltration were assessed in patients with esophageal squamous cell cancer (ESCC). CD47-overexpressing ESCC cell lines were selected and human M2 macrophage phagocytic activity was measured. The results revealed that CD47 is highly expressed and macrophages are markedly infiltrated in cancerous tissue compared with non-cancerous tissue. High CD47 expression was detected in ESCC cell lines and the results of a phagocytosis assay indicated that human M2 macrophages phagocytized tumor cells in a dose-dependent manner following the blocking of CD47-SIRPα signaling by anti-CD47 antibodies. The results of the present study therefore support the use of anti-CD47 immunotherapy to treat patients with ESCC.

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Section: Discussionsupporting

confidence: 49%

Characterization of cluster of differentiationï¿½47 expression and its potential as a therapeutic target in esophageal squamous cell cancer

Zhao

Wang

et al. 2017

Oncol Lett

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“…Of note, it has been reported that treatment with an anti-CD47 antibody effectively suppresses in vivo tumor growth without coadministration of other chemotherapeutic agents (38,39). Given that CD47 is a well-known "don't eat me" signal for inhibiting phagocytosis (40), the uptake of cancer cells by phagocytes is a promising target for anticancer therapy, particularly when combined with a method that accelerates the cancer cell phagocytosis.…”

Section: Discussionmentioning

confidence: 99%

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis

Kimura

Inoue

Hangai

et al. 2016

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

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Tumor metastasis is the cause of most cancer deaths. Although metastases can form in multiple end organs, the liver is recognized as a highly permissive organ. Nevertheless, there is evidence for immune cell-mediated mechanisms that function to suppress liver metastasis by certain tumors, although the underlying mechanisms for the suppression of metastasis remain elusive. Here, we show that Dectin-2, a C-type lectin receptor (CLR) family of innate receptors, is critical for the suppression of liver metastasis of cancer cells. We provide evidence that Dectin-2 functions in resident macrophages in the liver, known as Kupffer cells, to mediate the uptake and clearance of cancer cells. Interestingly, Kupffer cells are selectively endowed with Dectin-2-dependent phagocytotic activity, with neither bone marrow-derived macrophages nor alveolar macrophages showing this potential. Concordantly, subcutaneous primary tumor growth and lung metastasis are not affected by the absence of Dectin-2. In addition, macrophage C-type lectin, a CLR known to be complex with Dectin-2, also contributes to the suppression of liver metastasis. Collectively, these results highlight the hitherto poorly understood mechanism of Kupffer cell-mediated control of metastasis that is mediated by the CLR innate receptor family, with implications for the development of anticancer therapy targeting CLRs.liver metastasis | C-type lectin receptor | Dectin-2 | Kupffer cell | phagocytosis

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“…In this sense, blocking CD47-SIRPa signal transduction by monoclonal antibodies or fusion proteins could increase macrophage phagocytosis of cancer cells. Blockade of the CD47/SIRPa axis by monoclonal antibody is a potential immunotherapeutic strategy for acute myeloid leukemia (13), breast cancer (14), and small cell lung cancer (15). CD47 is also highly expressed on NSCLC cells (16,17).…”

Section: Introductionmentioning

confidence: 99%

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

Zhang

Fan

Wang

et al. 2017

Cancer Immunology Research

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CD47-specific antibodies and fusion proteins that block CD47-SIRPa signaling are employed as antitumor agents for several cancers. Here, we investigated the synergistic antitumor effect of simultaneously targeting CD47 and autophagy in nonsmall cell lung cancer (NSCLC). SIRPaD1-Fc, a novel CD47-targeting fusion protein, was generated and was found to increase the phagocytic and cytotoxic activities of macrophages against NSCLC cells. During this process, autophagy was markedly triggered, which was characterized by the three main stages of autophagic flux, including formation and accumulation of autophagosomes, fusion of autophagosomes with lysosomes, and degradation of autophagosomes in lysosomes. Meanwhile, reactive oxygen species and inactivation of mTOR were shown to be involved in autophagy initiation in SIRPaD1-Fc-treated cells, indicating a probable mechanism for autophagy activation after targeting CD47 by SIRPaD1-Fc. Inhibition of autophagy enhanced macrophage-mediated phagocytosis and cytotoxicity against SIRPaD1-Fc-treated NSCLC cells. In addition, simultaneously targeting both CD47 and autophagy in NSCLC xenograft models elicited enhanced antitumor effects, with recruitment of macrophages, activated caspase-3, and overproduction of ROS at the tumor site. Our data elucidated the cytoprotective role of autophagy in CD47-targeted therapy and highlighted the potential approach for NSCLC treatment by simultaneously targeting CD47 and autophagy.

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CD47-blocking immunotherapies stimulate macrophage-mediated destruction of small-cell lung cancer

Cited by 353 publications

References 55 publications

Characterization of cluster of differentiationï¿½47 expression and its potential as a therapeutic target in esophageal squamous cell cancer

Characterization of cluster of differentiationï¿½47 expression and its potential as a therapeutic target in esophageal squamous cell cancer

The innate immune receptor Dectin-2 mediates the phagocytosis of cancer cells by Kupffer cells for the suppression of liver metastasis

Targeting CD47 and Autophagy Elicited Enhanced Antitumor Effects in Non–Small Cell Lung Cancer

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