The “don't eat me” signal CD47 is a novel diagnostic biomarker and potential therapeutic target for diffuse malignant mesothelioma

Schürch, Christian M.; Förster, Stefan; Brühl, Frido; Yang, Sara; Felley‐Bosco, Emanuela; Hewer, Ekkehard

doi:10.1080/2162402x.2017.1373235

Cited by 40 publications

(33 citation statements)

References 53 publications

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“…CD47 can be expressed on many healthy cells in mice and humans and is highly expressed on a variety of CSCs, including both hematopoietic and solid tumors (145). Expression of CD47 in tumor cells avoid their recognition and elimination by macrophages, dendritic cells, and T cells and induces epithelialmesenchymal transition (EMT) through modulation of Ncadherin and E-cadherin (146).…”

Section: Impaired Dcs Recruitment: Ccl4 Inhibitionmentioning

confidence: 99%

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

et al. 2019

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WNT/β-catenin signaling is involved in many physiological processes. Its implication in embryonic development, cell migration, and polarization has been shown. Nevertheless, alterations in this signaling have also been related with pathological events such as sustaining and proliferating the cancer stem cell (CSC) subset present in the tumor bulk. Related with this, WNT signaling has been associated with the maintenance, expansion, and epithelial-mesenchymal transition of stem cells, and furthermore with two distinctive features of this tumor population: therapeutic resistance (MDR, multidrug resistance) and immune escape. These mechanisms are developed and maintained by WNT activation through the transcriptional control of the genes involved in such processes. This review focuses on the description of the best known WNT pathways and the molecules involved in them. Special attention is given to the WNT cascade proteins deregulated in tumors, which have a decisive role in tumor survival. Some of these proteins function as extrusion pumps that, in the course of chemotherapy, expel the drugs from the cells; others help the tumoral cells hide from the immune effector mechanisms. Among the WNT targets involved in drug resistance, the drug extrusion pump MDR-1 (P-GP, ABCB1) and the cell adhesion molecules from the CD44 family are highlighted. The chemokine CCL4 and the immune checkpoint proteins CD47 and PD-L1 are included in the list of WNT target molecules with a role in immunity escape. This pathway should be a main target in cancer therapy as WNT signaling activation is essential for tumor progression and survival, even in the presence of the anti-tumoral immune response and/or antineoplastic drugs. The appropriate design and combination of anti-tumoral strategies, based on the modulation of WNT mediators and/or protein targets, could negatively affect the growth of tumoral cells, improving the efficacy of these types of therapies.

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Section: Impaired Dcs Recruitment: Ccl4 Inhibitionmentioning

confidence: 99%

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

et al. 2019

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“…Numbers of stromal macrophages were positively correlated to the number of stromal Tregs ( R = 0.41, p = 0.002), suggesting that macrophages stimulate and recruit CD4+ cells by affecting the adaptive immune response [ 15 , 21 ]. Schürch et al found heavy infiltration of M2 macrophages in all 40 MPM analyzed [ 22 ]. Table 2 summarizes the extent of macrophage infiltration found in these studies.…”

Section: Macrophagesmentioning

confidence: 99%

Heterogeneity in Immune Cell Content in Malignant Pleural Mesothelioma

Minnema-Luiting

Vroman

Aerts

et al. 2018

IJMS

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Malignant pleural mesothelioma (MPM) is a highly aggressive cancer with limited therapy options and dismal prognosis. In recent years, the role of immune cells within the tumor microenvironment (TME) has become a major area of interest. In this review, we discuss the current knowledge of heterogeneity in immune cell content and checkpoint expression in MPM in relation to prognosis and prediction of treatment efficacy. Generally, immune-suppressive cells such as M2 macrophages, myeloid-derived suppressor cells and regulatory T cells are present within the TME, with extensive heterogeneity in cell numbers. Infiltration of effector cells such as cytotoxic T cells, natural killer cells and T helper cells is commonly found, also with substantial patient to patient heterogeneity. PD-L1 expression also varied greatly (16–65%). The infiltration of immune cells in tumor and associated stroma holds key prognostic and predictive implications. As such, there is a strong rationale for thoroughly mapping the TME to better target therapy in mesothelioma. Researchers should be aware of the extensive possibilities that exist for a tumor to evade the cytotoxic killing from the immune system. Therefore, no “one size fits all” treatment is likely to be found and focus should lie on the heterogeneity of the tumors and TME.

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“…An important function of CD47 is its role as a marker of self and a “don’t eat me” signal that inhibits phagocytosis by binding to signal regulatory protein α (SIRPα) on macrophages (Figure 3 C) ( 253 – 255 ). Overexpression of CD47 has been reported on numerous solid and hematological human cancers, and blocking CD47 promotes macrophage activation, enhances tumor cell phagocytosis and prolongs survival in murine cancer models ( 256 – 264 ). Importantly, CD47 is overexpressed on AML LSCs and further upregulated during their mobilization.…”

Section: Antibodies That Activate Antitumoral Innate Immunity: Tams Amentioning

confidence: 99%

Therapeutic Antibodies for Myeloid Neoplasms—Current Developments and Future Directions

Schürch

2018

Front. Oncol.

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Therapeutic monoclonal antibodies (mAbs) such as antibody–drug conjugates, ligand–receptor antagonists, immune checkpoint inhibitors and bispecific T cell engagers have shown impressive efficacy in the treatment of multiple human cancers. Numerous therapeutic mAbs that have been developed for myeloid neoplasms, including acute myeloid leukemia (AML) and myelodysplastic syndrome (MDS), are currently investigated in clinical trials. Because AML and MDS originate from malignantly transformed hematopoietic stem/progenitor cells—the so-called leukemic stem cells (LSCs) that are highly resistant to most standard drugs—these malignancies frequently relapse and have a high disease-specific mortality. Therefore, combining standard chemotherapy with antileukemic mAbs that specifically target malignant blasts and particularly LSCs or utilizing mAbs that reinforce antileukemic host immunity holds great promise for improving patient outcomes. This review provides an overview of therapeutic mAbs for AML and MDS. Antibody targets, the molecular mechanisms of action, the efficacy in preclinical leukemia models, and the results of clinical trials are discussed. New developments and future studies of therapeutic mAbs in myeloid neoplasms will advance our understanding of the immunobiology of these diseases and enhance current therapeutic strategies.

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The “don't eat me” signal CD47 is a novel diagnostic biomarker and potential therapeutic target for diffuse malignant mesothelioma

Cited by 40 publications

References 53 publications

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

WNT Signaling in Tumors: The Way to Evade Drugs and Immunity

Heterogeneity in Immune Cell Content in Malignant Pleural Mesothelioma

Therapeutic Antibodies for Myeloid Neoplasms—Current Developments and Future Directions

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