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Targeting Subgroup-specific Cancer Epitopes for Effective Treatment of Pediatric Medulloblastoma
Published in Surinder K. Batra, Moorthy P. Ponnusamy, Gene Regulation and Therapeutics for Cancer, 2021
Sidharth Mahapatra, Naveenkumar Perumall
Malignant cells have the capacity to evade immunologic surveillance through the expression of unique cell surface markers making them immune resistant. One of these markers that is highly expressed in a variety of tumor types, CD47, activates the signal regulatory protein alpha (SIRPoc) on myeloid cells, which in turn, protects the malignant cells from phagocytosis by macrophages [108]. Using the anti-CD47 antibody, Hu5F9-G4, authors demonstrated not only elevated tumor cell phagocytosis and growth inhibition but also an inhibition of neuroaxis spread in xenograft models of high MYC-expressing medulloblastoma [109]. Similarly, B7-H3 (CD276), which is an immune checkpoint member of the B7 family, plays a role in the functional inhibition of T-cells and is overexpressed in a variety of solid tumors, often correlated with poor prognosis [110]. A variety of clinical-translational advances have been made in B7-H3 targeting for cancer therapy, including blocking antibodies, bispecific antibodies, small molecule inhibitors, and chimeric antigen receptor T-cell (CAR T-cell) therapy [110, 111]. In an MYC-amplified medulloblastoma xenograft model, B7-H3 CAR T-cell infusion into the posterior fossa led to dramatic reduction in tumor burden and prolonged survival [111]. Finally, an emerging and provocative new approach to high-risk medulloblastoma treatment is exploiting telomerase targeting. By incorporating a telomerase substrate, 6-thio-dG, into the telomeres of tumor cells, authors demonstrated a dose-dependent inhibition of MB cell growth in vitro with reduced tumor sphere formation and elevated apoptosis [112].
Cell Membrane-Mimetic Nanoparticles for Cancer Treatment: What Has Been Done So Far?
Published in Hala Gali-Muhtasib, Racha Chouaib, Nanoparticle Drug Delivery Systems for Cancer Treatment, 2020
João Basso, Jessica Silva, Maria Mendes, João Sousa, Alberto Pais, Carla Vitorino
Several strategies have been developed to improve the performance of drug delivery systems, as they are quickly recognized as foreign bodies that trigger an immunological reaction leading to their quick removal from the bloodstream. The leading standard surface engineering approach is to pegylate these platforms, thus forming a hydration shell that is able to evade immune responses. Yet, it has been shown that after multiple administrations, pegylated nanosystems trigger anti-PEG responses, hence the need to explore new stealth moieties [15]. Erythrocytes are the major cellular component of blood, being characterized by their biconcave shape and absence of nucleus and other organelles. Moreover, erythrocytes have a life span of 100 to 120 days before undergoing senescence and clearance from the bloodstream by splenic macrophages, and this may be due to the presence of the integrin-associated transmembrane protein CD47 [16, 17]. In fact, erythrocytes lacking CD47 receptors on their surface are rapidly cleared from the blood circulation following a macrophage response [17].
Monocyte and lymphocyte membrane markers: Ontogeny and clinical significance
Published in Gabriel Virella, Medical Immunology, 2019
Scott Sugden, Damien Montamat-Sicotte, Karen K. Yam, Joseph Murphy, Bader Yassine Diab, Virginia Litwin
CD47 is expressed at higher levels on leukemia cells than on healthy cells. The surface protein targets signal regulatory protein α (SIRPα) on the surface of myeloid cells. CD47-SIRPα interaction inhibits macrophage phagocytosis, allowing cancer cells to escape immune surveillance. Current focus in immunotherapy has been targeted toward inhibiting CD47-SIRPα interaction via anti-CD47 antibodies. This activates innate immunity, promoting cancer cell destruction by macrophages. It also activates adaptive immunity by promoting antigen presentation, mostly by DCs, leading to antitumor cytotoxic reactions.
A patent review of glutaminyl cyclase inhibitors (2004–present)
Published in Expert Opinion on Therapeutic Patents, 2021
Judite R.M. Coimbra, Jorge A.R. Salvador
CD47 is an immune checkpoint broadly expressed that interacts with the transmembrane signal regulatory protein α (SIRPα) expressed on the surface of myeloid cells (macrophages and antigen-presenting cells) [54]. The interaction between CD47 and SIRPα mediates an innate immune tolerance, called a ‘don’t eat me’ signal, which ultimately inhibits phagocytosis and antigen presentation. CD47 expression is particularly increased on tumor cells as well as in cells involved in a variety of disorders, such as atherosclerosis, fibrotic diseases and infectious diseases [55]. Thus, CD47-SIRPα interaction downregulates both innate and adaptive immune response, which is a crucial way for tumor cells to escape from immune surveillance [56]. Crystallographic analysis of the CD47-SIRPα complex indicates the presence of CD47 N-terminal pE modification located in the CD47-SIRPα binding interface [57]. Evidence suggests that the formation of pE on CD47 protein depends on isoQC enzyme, and this modification is required for effective interaction [23,24]. Moreover, the reduction of isoQC activity by genetic deletion or pharmacological inhibition (using QC/isoQC inhibitors) led to an almost complete inhibition of pE post-translational modification and disruption of the binding of SIRPα and CD47, and improvement of the phagocytosis and clearance of cancer cells [23,24,58]. Thus, isoQC enzyme has been recognized as a regulator of the CD47-SIRPα pathway, and a novel and attractive target for cancer immunotherapy.
The role of macrophages and osteoclasts in the progression of leukemia
Published in Hematology, 2021
Kun Li, Runming Jin, Xiaoyan Wu
In addition to CSF1R inhibitors, another important target is CD47, a key ‘don’t eat me’ molecule that is upregulated by a variety of cancers[66,67]. CD47 renders malignant cells resistant to classic immune surveillance machinery and is now recognized as a fundamental driver of tumor growth. Under normal physiological conditions, the CD47 protein exists on the surface of many healthy cells. By combining with SIRPα (signal regulatory protein-α) on the surface of macrophages, CD47 tells macrophages not to ‘eat’ them, thereby protecting healthy cells from being eliminated. When cells age or become diseased, CD47 is gradually lost on the cell surface, and macrophages can recognize and process senescent or diseased cells. Unfortunately, many tumor cells also overexpress CD47; subsequently, TAMs not only coexist peacefully with tumor cells but also promote the proliferation of blood vessels in tumors, inhibit effector T cells, and promote tumor cell expansion and growth. At present, there are two main strategies for targeting the CD47-SIRPα pathway: via the CD47 antibody or via the SIRPα-Fc recombinant protein. Both methods have been validated by preclinical efficacy[68]. Tumor cells can promote the migration of MDSCs and macrophages to the tumor area by expressing chemokines CCL2, CCL5, CXCL12, etc. By blocking these recruitment pathways, the number of MDSCs and tumor-promoting macrophages in the tumor infiltration area can be reduced (Figure 1). However, whether targeting these pathways is useful for hematological tumors needs more research.
Tumor-associated macrophages and macrophage-related immune checkpoint expression in sarcomas
Published in OncoImmunology, 2020
Amanda R. Dancsok, Dongxia Gao, Anna F. Lee, Sonja Eriksson Steigen, Jean-Yves Blay, David M. Thomas, Robert G. Maki, Torsten O. Nielsen, Elizabeth G. Demicco
CD47 is a ubiquitously expressed cell-surface protein that protects viable erythrocytes from phagocytosis, sometimes referred to as the “don’t eat me” signal.24-30 In cancer, CD47 can be over-expressed to evade phagocyte-mediated anti-tumor immunity via interaction with SIRPα (signal-regulatory protein alpha), a cell-surface receptor expressed by macrophages and dendritic cells.31 Anti-CD47 monoclonal antibodies have impressive activity in mouse xenograft models,32-39 leading to the opening of clinical trials targeting the CD47/SIRPα axis. In phase 1 studies targeting CD47/SIRPα signaling, encouraging responses were seen in both lymphoma and advanced solid tumors.39-42 Overexpression of CD47 has been observed across most cancers,32-36,43-45 including in osteosarcoma,46 but has never been systematically examined in soft tissue sarcomas.