CD24: A Novel Target for Cancer Immunotherapy

Panagiotou, Emmanouil; Syrigos, Nikolaos; Charpidou, Andriani; Κοττέας, Ηλίας; Vathiotis, Ioannis

doi:10.3390/jpm12081235

Cited by 49 publications

(28 citation statements)

References 127 publications

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“…Currently, treatment targeting CD24 mainly includes three methods: monoclonal antibody, antibody-drug conjugates, and Chimeric Antigen Receptor T-cell therapy. [29,30] However, these methods do not change the expression of CD24 and only achieve transient signal inhibition. Therefore, there is an urgent need to develop new methods to treat cancer by altering the expression of CD24.…”

Section: Introductionmentioning

confidence: 99%

Nano‐LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec‐10 Signaling Pathway

Wang

Liu

et al. 2023

Advanced Science

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Lysosome‐targeting chimeras (LYTACs) are an emerging therapeutic modality that effectively degrade cancer cell membranes and extracellular target proteins. In this study, a nanosphere‐based LYTAC degradation system is developed. The amphiphilic peptide‐modified N‐acetylgalactosamine (GalNAc) can self‐assemble into nanospheres with a strong affinity for asialoglycoprotein receptor targets. They can degrade different membranes and extracellular proteins by linking with the relevant antibodies. CD24, a heavily glycosylated glycosylphosphatidylinositol‐anchored surface protein, interacts with Siglec‐10 to modulate the tumor immune response. The novel Nanosphere‐AntiCD24, synthesized by linking nanospheres with CD24 antibody, accurately regulates the degradation of CD24 protein and partially restores the phagocytic function of macrophages toward tumor cells by blocking the CD24/Siglec‐10 signaling pathway. When Nanosphere‐AntiCD24 is combined with glucose oxidase, an enzyme promoting the oxidative decomposition of glucose, the combination not only effectively restores the function of macrophages in vitro but also suppresses tumor growth in xenograft mouse models without detectable toxicity to normal tissues. The results indicate that GalNAc‐modified nanospheres, as a part of LYTACs, can be successfully internalized and are an effective drug‐loading platform and a modular degradation strategy for the lysosomal degradation of cell membrane and extracellular proteins, which can be broadly applied in the fields of biochemistry and tumor therapeutics.

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Section: Introductionmentioning

confidence: 99%

Nano‐LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec‐10 Signaling Pathway

Wang

Liu

et al. 2023

Advanced Science

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“…The CD24 primary function is to inhibit macrophage phagocytic capacity by binding Siglec-10 ( 28 ). Additionally, CD24 was suggested to be a tumor-initiating cell marker and has been described with additional functions as an adhesion molecule important for invasion and migration, as well as being capable of activating signaling pathways involved in tumor cell proliferation ( 52 – 54 ). Regarding the tumor immune microenvironment, Bockmayr et al.…”

Section: Discussionmentioning

confidence: 99%

Digital expression profile of immune checkpoint genes in medulloblastomas identifies CD24 and CD276 as putative immunotherapy targets

et al. 2023

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IntroductionMedulloblastoma is the most common and lethal pediatric malignant brain tumor. It comprises four main molecular subgroups: WNT-activated, SHH-activated, Group 3, and Group 4. Medulloblastoma treatment is surgical resection, craniospinal radiation, and chemotherapy. However, many patients do not respond to therapy, and most suffer severe side effects. Cancer immunotherapy targeting immune checkpoints (IC) (PD-1, PD-L1, and CTLA4) has been getting disappointing outcomes in brain tumors. Nevertheless, other less explored immune checkpoints may be promising candidates for medulloblastoma therapy.ObjectivesIn the present study, we aimed to characterize the expression profile of 19 immune checkpoints in medulloblastoma.MethodsWe analyzed 88 formalin-fixed paraffin-embedded medulloblastomas previously classified for each molecular subgroup and three non-tumoral brain tissue. mRNA levels of 19 immune checkpoint-related genes were quantified using the nCounter (PanCancer Immune Profiling Panel) assay. Further in silico analysis was performed in two larger public microarray datasets, one of which enabled comparisons between tumoral and non-tumoral tissues. Immunohistochemistry of PD-L1 was performed in a subset of cases. Microsatellite instability was also molecularly analyzed.ResultsWe observed an absence of expression of the canonic ICs, namely PDCD1 (PD-1), CD274 (PD-L1), and CTLA4, as well as CD80, CD86, BTLA, IDO1, CD48, TNFSF14, CD160, CEACAM1, and CD244. PD-L1 protein expression was also practically absent. We found higher mRNA levels of CD24, CD47, CD276 (B7-H3), and PVR, and lower mRNA levels of HAVCR2, LAG3, and TIGIT genes, with significant differences across the four molecular subgroups. Compared to the non-tumor tissues, the expression levels of CD276 in all subgroups and CD24 in SHH, Group 3, and Group 4 subgroups are significantly higher. The in silico analysis confirmed the expression profile found in the Brazilian cohort, including the lower/absent expression of the canonic ICs. Moreover, it confirmed the overexpression of CD24 and CD276 in medulloblastomas compared with the non-tumor tissue. Additionally, CD276 and CD24 high levels were associated with worse survival.ConclusionThese results highlight the low or absence of mRNA levels of the canonic targetable ICs in medulloblastomas. Importantly, the analysis revealed overexpression of CD24 and CD276, which can constitute prognostic biomarkers and attractive immunotherapy targets for medulloblastomas.

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“…Consequently, targeting GPAA1 and other components of the GPI synthesis pathway could be a feasible strategy for various CD24+ cancers, including breast, lung and colorectal cancers 9 .…”

Section: Discussionmentioning

confidence: 99%

“…Recent studies have identified the CD24-Siglec10 immune checkpoint as a promising therapeutic target in ovarian cancer. 9 CD24 is a highly glycosylated cell adhesion protein that is linked to the plasma membrane by a glycosylphosphatidylinositol (GPI) anchor. 9 CD24 is primarily expressed by immune cells but is often highly expressed in many cancers, most notably ovarian cancer.…”

Section: Introductionmentioning

confidence: 99%

Inhibiting the GPI Transamidase Subunit GPAA1 Abolishes CD24 Surface Localization and Enhances Macrophage-Mediated Phagocytosis of Ovarian Cancer Cells

Mishra,

Ye,

Banday

et al. 2023

Preprint

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The CD24-Siglec10 signaling axis is an immune checkpoint pathway that shields ovarian cancer cells from phagocytosis by tumor-associated macrophages (TAMs), making it an appealing immunotherapeutic target. Here, we investigate factors influencing CD24 cell surface expression and assess their suitability as drug targets. Using a CRISPR-based knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment-1) as a positive regulator of CD24 cell surface expression. GPAA1 is a crucial component of the multi-subunit GPI transamidase complex, which facilitates the attachment of the GPI lipid anchor to the C-terminus of CD24, enabling its surface localization. Reducing the activity of GPAA1 in ovarian cancer cells, either by genetic ablation or targeting with an aminopeptidase inhibitor bestatin, disrupts GPI attachment to CD24. This disruption impairs CD24 cell surface localization, enhances phagocytosis by TAMs, and suppresses tumor growth in mice. Our study highlights the potential of GPAA1 targeting as a therapeutic approach for CD24-positive ovarian cancers.

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CD24: A Novel Target for Cancer Immunotherapy

Cited by 49 publications

References 127 publications

Nano‐LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec‐10 Signaling Pathway

Nano‐LYTACs for Degradation of Membrane Proteins and Inhibition of CD24/Siglec‐10 Signaling Pathway

Digital expression profile of immune checkpoint genes in medulloblastomas identifies CD24 and CD276 as putative immunotherapy targets

Inhibiting the GPI Transamidase Subunit GPAA1 Abolishes CD24 Surface Localization and Enhances Macrophage-Mediated Phagocytosis of Ovarian Cancer Cells

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