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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].
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.
Mouse Models in Personalized Cancer Medicine
Published in II-Jin Kim, Cancer Genetics and Genomics for Personalized Medicine, 2017
M.E. Beaulieu, T. Jauset, D. Massó-Vallés, L. Soucek, J.R. Whitfield
NSG and NOG mice have increased HSC engraftment capacity compared to the BRG background, mainly in human T cells (Brehm et al., 2010). This is caused, at least in part, by a polymorphism in the gene encoding the signal regulatory protein alpha (SIRPα) receptor in the NOD background, which allows enhanced binding to the human CD47 ligand, whose expression on mouse macrophages supports human hematopoiesis (Takenaka et al., 2007). Those mice can be further “humanized” by engraftment with fetal thymus and liver from the same source in the kidney capsule. This model is known as NOD/SCID-hu BLT mice (abbreviated BLT) and is currently the humanized mouse model with the most functional immune system. Unlike mice transplanted with HSCs only, BLT mice present human mucosal immunity (Melkus et al., 2006).
The triglyceride-glucose index as a novel marker associated with sarcopenia in non-diabetic patients on maintenance hemodialysis
Published in Renal Failure, 2022
Ruoxin Chen, Liuping Zhang, Mengyan Zhang, Ying Wang, Dan Liu, Zuolin Li, Xiaoliang Zhang, Hui Jin, Bicheng Liu, Hong Liu
Insulin resistance is an independent risk factor for CKD [27] and is associated with skeletal muscle protein breakdown [22,28]. Thomas et al. [29] found that CKD-induced inflammatory cytokines stimulate nuclear factor (NF)-κB activation, allowing increased expression of signal regulatory protein-α (SIRP-α) proteins. In addition, SIRP-α interacts with insulin receptors and insulin receptor substrate-1, which can reduce tyrosine phosphorylation, ultimately impairing intracellular insulin signaling and inducing muscle wasting. Moreover, the accumulation of uremic toxins, metabolic acidosis, and persistent micro-inflammatory state are unique factors that aggravate insulin resistance in patients with CKD [11,13]. Given the close pathophysiological relationship between sarcopenia and insulin resistance [10,28,30], the association between the TyG index and sarcopenia in patients undergoing MHD is plausible.
Targeting the tumor microenvironment in cholangiocarcinoma: implications for therapy
Published in Expert Opinion on Investigational Drugs, 2021
In light of their pro-tumor role across a variety of malignancies, therapeutic targeting of TAMs has become an attractive anti-cancer approach. TAM depletion results in inhibition of WNT signaling with a resultant reduction in tumor burden in preclinical models of CCA [14]. There are several different approaches to inhibit or deplete TAMs in cancer, and various TAM targeting strategies are currently under investigation [15]. However, a recent study demonstrated that TAM blockade alone does not lead to tumor suppression in CCA due to a compensatory emergence of granulocytic-myeloid-derived suppressor cells (G-MDSCs) [16]. Cluster of differentiation 47 (CD47) is overexpressed in a number of different tumor types, and plays a role in tumor progression and metastasis via interaction with signal regulatory protein alpha (SIRPα), mainly expressed on macrophages. The CD47/SIRPα axis functions as a protective signal employed by cancer cells to avoid phagocytic elimination [17]. CD47 has emerged as a myeloid checkpoint, and targeting the CD47/SIRPα axis has garnered attention of late [18–20]. Administration of anti-CD47 (B6H12.2) antibody decreased CCA colonization and infiltration of TAM in a mouse model of CCA [21]. By demonstrating that disruption of the CD47-SIRPα interaction promotes phagocytosis of tumor cells in CCA, this study indicated that CD47 may be a potential therapeutic target in CCA.
An immune-based risk-stratification system for predicting prognosis in pulmonary sarcomatoid carcinoma (PSC)
Published in OncoImmunology, 2021
Haoyue Guo, Binglei Li, Li Diao, Hao Wang, Peixin Chen, Minlin Jiang, Lishu Zhao, Yayi He, Caicun Zhou
Considering the suppressive effect of tumor-associated innate immune cells on anti-tumor immunity, the blockade of innate immune checkpoints has been proposed. CD47 and CD24 are two innate immune checkpoints in the spotlight. A research team from Stanford revealed that the combination of CD47 on TC and signal-regulatory protein α (SIRPα) on macrophages could dramatically weaken the phagocytic ability of macrophages.60–66 The inhibition of the CD47-SIRPα pathway reduced the tumor growth by enhancing the killing effect of innate immunity and has been applied in multiple cancers preclinically.63–66 Meanwhile, CD24 was another novel checkpoint on TCs, which could specifically combine with sialic-acid-binding Ig-like lectin 10 (Siglec-10) on macrophages.67 The CD24-Siglec-10 pathway negatively regulates the danger-associated molecular patterns (DAMPs) signaling,68 which is essential for recruiting inflammatory macrophages. Interestingly, the expression of CD24 significantly increased with the inhabitation of CD4767. Thus, the inhibition of CD47 and (or) CD24 should be the focus of future PSC innate immunotherapy research.