CD47 protein expression in acute myeloid leukemia: A tissue microarray-based analysis

Galli, Serena; Zlobec, Inti; Schürch, Christian M.; Perren, Aurel; Ochsenbein, Adrian F.; Banz, Yara

doi:10.1016/j.leukres.2015.04.007

Cited by 50 publications

(42 citation statements)

References 16 publications

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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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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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“…Similarly to CD33, CD47 is overexpressed on AML bulk cells and AML LSCs [8, 28]. Expression of CD47 contributes to tumor progression by enabling AML cells to evade phagocytosis and is consequently correlated with a poor prognosis [8].…”

Section: Introductionmentioning

confidence: 99%

SIRPα-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells

et al. 2017

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CD47, expressed on a variety of tumor cells, confers immune resistance by delivering an inhibitory “don't eat me” signal to phagocytic cells via its myeloid-specific receptor SIRPα. Recent studies have shown that blocking the CD47-SIRPα axis with CD47-directed antibodies or antibody-derivatives enhances phagocytosis and increases antitumor immune effects. However, CD47 expression on healthy cells creates an antigen sink and potential sites of toxicity, limiting the efficacy of CD47-directed therapies. In this study, we first characterized CD47 expression in Acute Myeloid Leukemia (AML) patients (n = 213) and found that CD47 is highly expressed on both AML bulk and stem cells irrespective of the disease state. Furthermore, to inhibit the CD47-SIRPα signaling pathway at the tumor site, we developed a so-called local inhibitory checkpoint monoclonal antibody (licMAB) by grafting the endogenous SIRPα domain to the N-terminus of the light chain of an antibody targeting CD33, a surface antigen expressed in AML. LicMABs selectively bind CD33-expressing cells even in the presence of a large CD33-negative CD47-positive antigen sink, stimulate phagocytosis of AML cells and eliminate AML cell lines and primary, patient-derived AML cells. Our findings qualify licMABs as a promising therapeutic approach to confine the benefit of disrupting the CD47-SIRPα axis to tumor antigen-expressing cells.

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“…In this way, CD47 serves as a “don’t eat me signal” and a marker of self, as loss of CD47 leads to homeostatic phagocytosis of aged or damaged cells [3]. Thus, when CD-47 protein is expressed on the surface of solid tumor cells, it serves as a potent signal to aid escape from immune surveillance [4]. This enables tumor cells to grow and divide uninterrupted by avoiding yet another host immune mechanism.…”

Section: Introductionmentioning

confidence: 99%

The CD47 “don't eat me signal” is highly expressed in human ovarian cancer

Brightwell

Grzankowski

Lele

et al. 2016

Gynecologic Oncology

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Objectives The CD47 “don’t eat me” signal allows tumor immune evasion. We tested the association of CD47 expression with outcomes in EOC. Methods CD47 expression was examined within the TCGA database for ovarian carcinoma. For validation, IHC was performed on a TMA consisting of specimens from 265 patients with EOC. The medical records of the patients were also retrospectively reviewed to correlate demographic and survival data. Results CD47 was amplified in 15/316 (5%) ovarian serous cancers in TCGA. In the validation cohort, the majority of patients had stage III/IV disease (208/265, 78.4%). CD47 expression was seen in 210/265 (79.2%). Patients were categorized into CD47hi (129/265; 48.7%) versus CD47lo (136/265; 51.3%). Patients with CD47lo tumors were more likely to have a complete response to adjuvant therapy than CD47hi (65% vs 50%, p= 0.026). Although there was a trend towards an increase in median OS (37.64 vs 45.26 mos, p=0.92) in the CD47lo group compared with CD47hi, the difference was not significant. Conclusions CD47 is expressed at high frequency in EOC. Patients with CD47lo EOC had a better treatment response to standard therapy, and trended towards improved OS. This demonstrates that while CD47 may be an immunologic shield that may be considered for targeted therapies, it is likely that it operates in concert with other mechanisms of immune evasion. Future studies to evaluate CD47 expression with other known mechanisms of immune escape in the tumor microenvironment may help further define its role.

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CD47 protein expression in acute myeloid leukemia: A tissue microarray-based analysis

Cited by 50 publications

References 16 publications

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

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

SIRPα-antibody fusion proteins stimulate phagocytosis and promote elimination of acute myeloid leukemia cells

The CD47 “don't eat me signal” is highly expressed in human ovarian cancer

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