LncRNA IL21-AS1 facilitates tumour progression by enhancing CD24-induced phagocytosis inhibition and tumorigenesis in ovarian cancer.

CD24 is overexpressed in various tumours and considered a regulator of cell migration, invasion, and proliferation. Recent studies have found that CD24 on ovarian cancer (OC) and triple-negative breast cancer cells interacts with the inhibitory receptor sialic-acid-binding Ig-like lectin 10 (Siglec-10) on tumour-associated macrophages (TAMs) to inhibit phagocytosis by macrophages. Because of its multiple roles in regulating the immune response and tumorigenesis, CD24 is a very promising therapeutic target. However, the regulatory mechanism of CD24 in OC remains unclear. Here, we found that the long noncoding RNA (lncRNA) IL21-AS1, which was upregulated in OC, inhibited macrophage-mediated phagocytosis and promoted OC cell proliferation and apoptosis inhibition. More importantly, after IL21-AS1 knockdown, a significant survival advantage was observed in mice engrafted with tumours. Mechanistically, we identified IL21-AS1 as a hypoxia-induced lncRNA. Moreover, IL21-AS1 increased HIF1α-induced CD24 expression under hypoxic conditions. In parallel, we found that IL21-AS1 acted as a competing endogenous RNA (ceRNA) for miR-561-5p to regulate CD24 expression. Finally, IL21-AS1 increased CD24 expression in OC and facilitated OC progression. Our findings provide a molecular basis for the regulation of CD24, thus highlighting a potential strategy for targeted treatment of OC.

EpCAM-CD24+ circulating cells associated with poor prognosis in breast cancer patients.

Following the discovery of circulating tumor cells (CTCs) in the peripheral blood of cancer patients, CTCs were initially postulated to hold promise as a valuable prognostic tool through liquid biopsy. However, a decade and a half of accumulated data have revealed significant complexities in the investigation of CTCs. A challenging aspect lies in the reduced expression or complete loss of key epithelial markers during the epithelial-mesenchymal transition (EMT). This likely hampers the identification of a pathogenetically significant subset of CTCs. Nevertheless, there is a growing body of evidence regarding the prognostic value of such molecules as CD24 expressing in the primary breast tumor. Herewith, the exact relevance of CD24 expression on CTCs remains unclear. We used two epithelial markers (EpCAM and cytokeratin 7/8) to assess the count of CTCs in 57 breast cancer patients, both with (M0mts) and without metastasis (M0) during the follow-up period, as well as in M1 breast cancer patients. However, the investigation of these epithelial markers proved ineffective in identifying cell population expressing different combinations of EpCAM and cytokeratin 7/8 with prognostic significance for breast cancer metastases. Surprisingly, we found CD24+ circulating cells (CCs) in peripheral blood of breast cancer patients which have no epithelial markers (EpCAM and cytokeratin 7/8) but was strongly associated with distant metastasis. Namely, the count of CD45-EpCAM-CK7/8-CD24+ N-cadherin-CCs was elevated in both groups of patients, those with existing metastasis and those who developed metastases during the follow-up period. Simultaneously, an elevation in these cell counts beyond the established threshold of 218.3 cells per 1 mL of blood in patients prior to any treatment predicted a 12-fold risk of metastases, along with a threefold decrease in distant metastasis-free survival over a 90-month follow-up period. The origin of CD45-EpCAM-CK7/8-CD24+ N-cadherin-CCs remains unclear. In our opinion their existence can be explained by two most probable hypotheses. These cells could exhibit a terminal EMT phenotype, or it might be immature cells originating from the bone marrow. Nonetheless, if this hypothesis holds true, it's worth noting that the mentioned CCs do not align with any of the recognized stages of monocyte or neutrophil maturation, primarily due to the presence of CD45 expression in the myeloid cells. The results suggest the presence in the peripheral blood of patients with metastasis (both during the follow-up period and prior to inclusion in the study) of a cell population with a currently unspecified origin, possibly arising from both myeloid and tumor sources, as confirmed by the presence of aneuploidy.

The safety and potential efficacy of exosomes overexpressing CD24 (EXO-CD24) in mild-moderate COVID-19 related ARDS.

INTRODUCTION: EXO-CD24 are exosomes genetically manipulated to over-express Cluster of Differentiation (CD) 24. It consists of two breakthrough technologies: CD24, the drug, as a novel immunomodulator that is smarter than steroids without any side effects, and exosomes as the ideal natural drug carrier. METHODS: A randomized, single blind, dose-finding phase IIb trial in hospitalized patients with mild to moderate Coronavirus disease 2019 (COVID-19) related Acute Respiratory Distress Syndrome (ARDS) was carried out in two medical centers in Athens. Patients received either 109 or 1010 exosome particles of EXO-CD24, daily, for five consecutive days and monitored for 28 days. Efficacy was assessed at day 7 among 91 patients who underwent randomization. The outcome was also compared in a post-hoc analysis with an income control group (n = 202) that fit the inclusion and exclusion criteria. RESULTS: The mean age was 49.4 (± 13.2) years and 74.4% were male. By day 7, 83.7% showed improved respiratory signs and 64% had better oxygen saturation (SpO2) (p < 0.05). There were significant reductions in all inflammatory markers, most notably in C-reactive protein (CRP), lactate dehydrogenase (LDH), ferritin, fibrinogen and an array of cytokines. Conversely, levels of the anti-inflammatory cytokine Interleukin-10 (IL-10) were increased (p < 0.05). Of all the documented adverse events, none were considered treatment related. No drug-drug interactions were noted. Two patients succumbed to COVID-19. Post-hoc analysis revealed that EXO-CD24 patients exhibited greater improvements in clinical and laboratory outcomes compared to an observational income control group. CONCLUSIONS: EXO-CD24 presents a promising therapeutic approach for hyper-inflammatory state and in particular ARDS. Its unique combination of exosomes, as a drug carrier, and CD24, as an immunomodulator, coupled with inhalation administration, warrants further investigation in a larger, international, randomized, quadri-blind trial against a placebo.

Targeting the GPI transamidase subunit GPAA1 abrogates the CD24 immune checkpoint in ovarian cancer.

CD24 is frequently overexpressed in ovarian cancer and promotes immune evasion by interacting with its receptor Siglec10, present on tumor-associated macrophages, providing a "don't eat me" signal that prevents targeting and phagocytosis by macrophages. Factors promoting CD24 expression could represent novel immunotherapeutic targets for ovarian cancer. Here, using a genome-wide CRISPR knockout screen, we identify GPAA1 (glycosylphosphatidylinositol anchor attachment 1), a factor that catalyzes the attachment of a glycosylphosphatidylinositol (GPI) lipid anchor to substrate proteins, as a positive regulator of CD24 cell surface expression. Genetic ablation of GPAA1 abolishes CD24 cell surface expression, enhances macrophage-mediated phagocytosis, and inhibits ovarian tumor growth in mice. GPAA1 shares structural similarities with aminopeptidases. Consequently, we show that bestatin, a clinically advanced aminopeptidase inhibitor, binds to GPAA1 and blocks GPI attachment, resulting in reduced CD24 cell surface expression, increased macrophage-mediated phagocytosis, and suppressed growth of ovarian tumors. Our study highlights the potential of targeting GPAA1 as an immunotherapeutic approach for CD24+ ovarian cancers.

Molecular mechanisms of Asparagus racemosus willd. and Withania somnifera (L.) Dunal as chemotherapeutic adjuvants for breast cancer treatment.

ETHNOPHARMACOLOGICAL RELEVANCE: Despite various treatment modalities, the progression and metastasis of breast cancer (BC) are grave concerns due to the alarming disease-free survival rate (DFS) and overall survival rate (OS) of affected patients. Over the years, many antibiotics, synthetic compounds, medicinal plant isolates and polyherbal combinations have been used as adjuvants in therapy for the management of primary and secondary tumors. Paclitaxel (PTX)-based chemotherapy for breast cancer causes multiple adverse side effects in patients. Withania somnifera (L.) Dunal (WS) and Asparagus racemosus Willd. (AR) as Ayurveda-inspired plant-based adjuvants were investigated for their anticancer effects on MDA-MB-231 and 4T1 cells in mouse model systems. AIM OF THE STUDY: This study focused on evaluating the adjuvant properties of WS and AR plant extracts with PTX and their effectiveness over PTX alone in terms of tumor inhibition. MATERIALS AND METHODS: The effects of WS and AR on DNA double-strand breaks (DSBs), senescence induction and mitochondrial functions were evaluated in BC cells in vitro. The potential for cancer stem cell (CSC) inhibition was evaluated via mammosphere formation assays and CD44/CD24 immunostaining. In vivo tumor growth studies were conducted in athymic BALB/c mice for MDA-MB-231 cells and in BALB/c mice for 4T1 cells. RESULTS: Induction of senescence was evident due to DSBs induced by the WS and AR extracts. Mammosphere formation and CD44/CD24 CSC markers were reduced after treatment with WS, AR or the combination of both in MCF-7 cells. WS or AR inhibited epithelial-to-mesenchymal transition (EMT). In vivo studies demonstrated that tumor growth inhibition was more pronounced in the treated group than in the PTX alone group and the untreated control group. CONCLUSION: Our study showed that the use of WS or AR plant hydroalcoholic extracts in combination with paclitaxel (PTX) has better effects on sensitivity and efficacy than PTX alone, as demonstrated in in vitro BC cells and mouse models with BC cell grafts. Hence, scheduling adjuvant therapy with WS or AR alone or combined with PTX can be advantageous for the management of triple-negative BC (TNBC). Further studies are warranted in human clinical conditions to ascertain the efficacy of these treatments.

Dual-Aptamer Recognition of DNA Logic Gate Sensor-Based Specific Exosomal Proteins for Ovarian Cancer Diagnosis.

Clinical diagnosis of ovarian cancer lacks high accuracy due to the weak selection of specific biomarkers along with the circumstance biomarkers localization. Clustering analysis of proteins transported on exosomes enables a more precise screening of effective biomarkers. Herein, through bioinformatics analysis of ovarian cancer and exosome proteomes, two coexpressed proteins, EpCAM and CD24, specifically enriched, were identified, together with the development of an as-derived dual-aptamer targeted exosome-based strategy for ovarian cancer screening. In brief, a DNA ternary polymer with aptamers targeting EpCAM and CD24 was designed to present a logic gate reaction upon recognizing ovarian cancer exosomes, triggering a rolling circle amplification chemiluminescent signal. A dynamic detection range of 6 orders of magnitude was achieved by quantifying exosomes. Moreover, for clinical samples, this strategy could accurately differentiate exosomes from healthy persons, other cancer patients, and ovarian cancer patients, enabling promising in situ detection. By accurately selecting biomarkers and constructing a dual-targeted exosomal protein detection strategy, the limitation of insufficient specificity of traditional protein markers was circumvented. This work contributed to the development of exosome-based prognosis monitoring in ovarian cancer through the identification of disease-specific exosome protein markers.

Site-specific Antibody-Nitric Oxide Conjugate HN02 Possesses Improved Antineoplastic and Safety Properties.

Antibody-drug conjugates (ADCs) combine the high specificity of antibodies with the cytotoxicity of payloads and have great potential in pan-cancer immunotherapy. However, the current payloads for clinical uses have limited the therapeutic window due to their uncontrollable off-site toxicity. There is unmet needs to develop more potent ADC payloads with better safety and efficacy profiles. Nitric oxide (NO) is a special molecule that has low toxicity itself, which can kill tumor cells effectively when highly concentrated, has broad application prospects. Previously, we prepared for the first time an antibody-nitric oxide conjugate (ANC)-HN01, which showed inhibitory activity against hepatocellular carcinoma. However, the random conjugation method made HN01 highly heterogeneous and unstable. Here, we used site-specific conjugation-based engineered cysteine sites (CL-V211C) of anti-CD24 antibody to prepare a second-generation ANC with a drug-to-antibody ratio of 2. The homogeneous ANC, HN02 was stable in human plasma, shown in vitro bystander effect to neighboring cells and antiproliferative activity to CD24-targeted tumor cells. Compared with HN01, HN02 significantly prolonged the survival of tumor-bearing mice. In summary, we developed a stable and homogeneous site-specific conjugated ANC, which showed good antitumor activity and improved safety profile both in vitro and in vivo. This study provides new insight into the development of next generation of ADC candidates.

Integration of multiomics analyses reveals unique insights into CD24-mediated immunosuppressive tumor microenvironment of breast cancer.

BACKGROUND: Tumor immunotherapy brings new light and vitality to breast cancer patients, but low response rate and limitations of therapeutic targets become major obstacles to its clinical application. Recent studies have shown that CD24 is involved in an important process of tumor immune regulation in breast cancer and is a promising target for immunotherapy. METHODS: In this study, singleR was used to annotate each cell subpopulation after t-distributed stochastic neighbor embedding (t-SNE) methods. Pseudo-time trace analysis and cell communication were analyzed by Monocle2 package and CellChat, respectively. A prognostic model based on CD24-related genes was constructed using several machine learning methods. Multiple quantitative immunofluorescence (MQIF) was used to evaluate the spatial relationship between CD24+PANCK+cells and exhausted CD8+T cells. RESULTS: Based on the scRNA-seq analysis, 1488 CD24-related differential genes were identified, and a risk model consisting of 15 prognostic characteristic genes was constructed by combining the bulk RNA-seq data. Patients were divided into high- and low-risk groups based on the median risk score. Immune landscape analysis showed that the low-risk group showed higher infiltration of immune-promoting cells and stronger immune reactivity. The results of cell communication demonstrated a strong interaction between CD24+epithelial cells and CD8+T cells. Subsequent MQIF demonstrated a strong interaction between CD24+PANCK+ and exhausted CD8+T cells with FOXP3+ in breast cancer. Additionally, CD24+PANCK+ and CD8+FOXP3+T cells were positively associated with lower survival rates. CONCLUSION: This study highlights the importance of CD24+breast cancer cells in clinical prognosis and immunosuppressive microenvironment, which may provide a new direction for improving patient outcomes.

Checkpoint CD24 function on tumor and immunotherapy.

CD24 is a protein found on the surface of cells that plays a crucial role in the proliferation, invasion, and spread of cancer cells. It adheres to cell membranes through glycosylphosphatidylinositol (GPI) and is associated with the prognosis and survival rate of cancer patients. CD24 interacts with the inhibitory receptor Siglec-10 that is present on immune cells like natural killer cells and macrophages, leading to the inhibition of natural killer cell cytotoxicity and macrophage-mediated phagocytosis. This interaction helps tumor cells escape immune detection and attack. Although the use of CD24 as a immune checkpoint receptor target for cancer immunotherapy is still in its early stages, clinical trials have shown promising results. Monoclonal antibodies targeting CD24 have been found to be well-tolerated and safe. Other preclinical studies are exploring the use of chimeric antigen receptor (CAR) T cells, antibody-drug conjugates, and gene therapy to target CD24 and enhance the immune response against tumors. In summary, this review focuses on the role of CD24 in the immune system and provides evidence for CD24 as a promising immune checkpoint for cancer immunotherapy.

Unraveling the role of CD24 in Hepatocellular carcinoma: Involvement of inactivated Hippo signaling and SOX4-mediated regulation.

Hepatocellular carcinoma (HCC) is a prevalent type of liver cancer, and CD24 gene is reportedly involved in HCC progression. However, the precise regulatory mechanisms of CD24 in HCC remain unclear. In this study, we established a primary HCC mouse model and observed that CD24, induced by inactivation of the Hippo pathway, was highly expressed in HCC. Using a systematic molecular and genomic approach, we identified the Hippo-YAP1-SOX4 pathway as the mechanism through which YAP1 induces CD24 upregulation in HCC cells. CD24 knockdown significantly attenuated YAP1 activation-induced HCC. These findings shed light on the link between CD24 and HCC progression, particularly in the Hippo-inactivated subclass of HCC. Therefore, CD24 may serve as a potential target for specific treatment of this HCC subclass.

VGLL1 stabilization of cytoplasmic TAZ promotes EGFR expression and maintains tumor initiating cells in breast cancer independent of TEAD.

Vestigial-like family member 1 (VGLL1) is one of the X-linked genes whose expression is elevated in basal-like breast cancer (BLBC) because of X-chromosome isodisomy. As an approach towards understanding its function, we performed correlation study using transcript data of breast cancer patients from cBioPortal for Cancer Genomics. Our analysis identified EGFR as the most correlated transcript with VGLL1. We demonstrate that VGLL1 promotes EGFR expression and increases the frequency of breast tumor initiating cells (CD44high/+CD24low/-). These findings are crucial because an elevated EGFR expression and high frequency of CD44high/+CD24low/- cells are defining features of BLBC, and we provide a new mechanistic insight into how their expressions are controlled. Importantly, VGLL1 regulation of EGFR and CD44high/+CD24low/- population is mediated by the hippo-transducer TAZ which exerts its oncogenic roles by binding and activating TEAD transcription factors. A crucial finding is that TEAD-binding domain of TAZ is dispensable for its regulation of EGFR and CD44high/+CD24low/- cells. Instead, VGLL1 stabilization of cytoplasmic TAZ is essential for these functions. Also, we show that VGLL1/TAZ restricts the surface expression of CD24 which contributes to the increased number of CD44high/+CD24low/- cells. In addition, we observed that VGLL1 represses AXL expression and suppresses claudin-low phenotype, and that is caused by the VGLL1 mediated nuclear expulsion of TAZ. Therefore, EGFR and AXL seem to represent two different breast tumor subtypes, and their differential expressions is controlled by VGLL1.

Role of CD44 and CD24 Expression on 2-years Disease Free Survival in Patients with Advanced Epithelial Ovarian Carcinoma.

OBJECTIVE: Ovarian cancer is one of the most common cancers with a high mortality rate worldwide. Despite optimal surgical therapy and chemotherapy, recurrence is still common. Cancer stem cells expressing CD44 and CD24 are thought to be contributing factors in recurrence. METHODS: A cohort retrospective study with survival analysis was carried out on advanced ovarian cancer patients who underwent optimal debulking surgery followed by 6 cycles of chemotherapy at Cipto Mangunkusumo General Hospital and Fatmawati General Hospital from January 2019 to March 2023. Immunohistochemical examination was performed on tumor tissue with CD44 and CD24 expression were assessed using the H-Score method then determined the cut off-point expression level using the ROC curve. Furthermore, the relationship between these expression levels with the disease-free survival was assessed using the survival curve. RESULTS: There were 48 subjects who were included in the study. There were high expression levels of CD44 in 47.9% and CD24 in 50% of cases. High CD44 expression had mean and median survival of 13.2 ± 1.8 and 11 months (HR 5.05, 95% CI 1.84- 13.85). High CD24 expression had mean and median survival of 13.5 ± 2.4 and 7 months (HR 7.73, 95% CI 2.58 - 23.15). The combination of the two high expressions had mean and median survival of 10.44 ± 1.88 and 7 months. CONCLUSION: High expression of CD44 and CD24 will shorten the disease-free survival of patients with advanced ovarian cancer.

CD24 negativity reprograms mitochondrial metabolism to PPARα and NF-κB-driven fatty acid ß-oxidation in triple-negative breast cancer.

CD24 is a well-characterized breast cancer (BC) stem cell (BCSC) marker. Primary breast tumor cells having CD24-negativity together with CD44-positivity is known to maintain high metastatic potential. However, the functional role of CD24 gene in triple-negative BC (TNBC), an aggressive subtype of BC, is not well understood. While the significance of CD24 in regulating immune pathways is well recognized in previous studies, the significance of CD24 low expression in onco-signaling and metabolic rewiring is largely unknown. Using CD24 knock-down and over-expression TNBC models, our in vitro and in vivo analysis suggest that CD24 is a tumor suppressor in metastatic TNBC. Comprehensive in silico gene expression analysis of breast tumors followed by lipidomic and metabolomic analyses of CD24-modulated cells revealed that CD24 negativity induces mitochondrial oxidative phosphorylation and reprograms TNBC metabolism toward the fatty acid beta-oxidation (FAO) pathway. CD24 silencing activates PPARα-mediated regulation of FAO in TNBC cells. Further analysis using reverse-phase protein array and its validation using CD24-modulated TNBC cells and xenograft models nominated CD24-NF-κB-CPT1A signaling pathway as the central regulatory mechanism of CD24-mediated FAO activity. Overall, our study proposes a novel role of CD24 in metabolic reprogramming that can open new avenues for the treatment strategies for patients with metastatic TNBC.

The response of CD27+CD38+ plasmablasts, CD24hiCD38hi transitional B cells, CXCR5-ICOS+PD-1+ Tph, Tph2 and Tfh2 subtypes to allergens in children with allergic asthma.

BACKGROUND: Allergic asthma is a type I allergic reaction mediated by serum Immunoglobulin E (IgE). B cell-mediated humoral immune response to allergens in the pathophysiology of allergic asthma have not been thoroughly elucidated. Peripheral helper T cells (Tph) and follicular helper T cells (Tfh) promote B cell differentiation and antibody production in inflamed tissues. OBJECTIVE: To investigate the roles of B cell subsets, Tph cell subsets and Tfh cell subsets in allergic immune responses. METHODS: Circulating B cell subsets, Tph cell subsets and Tfh cell subsets in 33 children with allergic asthma and 17 healthy children were analyzed using multicolor flow cytometry. The level of serum total IgE was also assessed. RESULTS: Our study found that CD27+CD38+ plasmablasts and CD24hiCD38hi transitional B cells increased and were correlated with serum total IgE level, CD27- naive B cells and CD24hiCD27+ B cells decreased in children with allergic asthma. CXCR5- Tph, CXCR5-ICOS+ Tph, CXCR5-ICOS+PD-1+ Tph, CXCR5+ICOS+ Tfh and CXCR5+ICOS+PD-1+ Tfh increased in children with allergic asthma. Further analysis showed increased Tph2, Tph17, Tfh2 and Tfh17 subtypes while decreased Tph1 and Tfh1 subtypes in children with allergic asthma. Most interestingly, Tph2 or Tfh2 subtypes had a positive correlation with serum total IgE level. CONCLUSION: Overall, these results provide insight into the allergens elicited B, Tph or Tfh cell response and identify heretofore unappreciated CD24hiCD38hi transitional B cells, CD24hiCD27+ B cells, CXCR5- Tph, CXCR5-ICOS+PD-1+ Tph, Tph2 subtypes and Tfh2 subtypes response to allergens.

Bispecific BCMA/CD24 CAR-T cells control multiple myeloma growth.

Anti-multiple myeloma B cell maturation antigen (BCMA)-specific chimeric antigen receptor (CAR) T-cell therapies represent a promising treatment strategy with high response rates in myeloma. However, durable cures following anti-BCMA CAR-T cell treatment of myeloma are rare. One potential reason is that a small subset of minimal residual myeloma cells seeds relapse. Residual myeloma cells following BCMA-CAR-T-mediated treatment show less-differentiated features and express stem-like genes, including CD24. CD24-positive myeloma cells represent a large fraction of residual myeloma cells after BCMA-CAR-T therapy. In this work, we develop CD24-CAR-T cells and test their ability to eliminate myeloma cells. We find that CD24-CAR-T cells block the CD24-Siglec-10 pathway, thereby enhancing macrophage phagocytic clearance of myeloma cells. Additionally, CD24-CAR-T cells polarize macrophages to a M1-like phenotype. A dual-targeted BCMA-CD24-CAR-T exhibits improved efficacy compared to monospecific BCMA-CAR-T-cell therapy. This work presents an immunotherapeutic approach that targets myeloma cells and promotes tumor cell clearance by macrophages.

Preclinical Repurposing of Sitagliptin as a Drug Candidate for Colorectal Cancer by Targeting CD24/CTNNB1/SOX4-Centered Signaling Hub.

Despite significant advances in treatment modalities, colorectal cancer (CRC) remains a poorly understood and highly lethal malignancy worldwide. Cancer stem cells (CSCs) and the tumor microenvironment (TME) have been shown to play critical roles in initiating and promoting CRC progression, metastasis, and treatment resistance. Therefore, a better understanding of the underlying mechanisms contributing to the generation and maintenance of CSCs is crucial to developing CSC-specific therapeutics and improving the current standard of care for CRC patients. To this end, we used a bioinformatics approach to identify increased CD24/SOX4 expression in CRC samples associated with poor prognosis. We also discovered a novel population of tumor-infiltrating CD24+ cancer-associated fibroblasts (CAFs), suggesting that the CD24/SOX4-centered signaling hub could be a potential therapeutic target. Pathway networking analysis revealed a connection between the CD24/SOX4-centered signaling, ß-catenin, and DPP4. Emerging evidence indicates that DPP4 plays a role in CRC initiation and progression, implicating its involvement in generating CSCs. Based on these bioinformatics data, we investigated whether sitagliptin, a DPP4 inhibitor and diabetic drug, could be repurposed to inhibit colon CSCs. Using a molecular docking approach, we demonstrated that sitagliptin targeted CD24/SOX4-centered signaling molecules with high affinity. In vitro experimental data showed that sitagliptin treatment suppressed CRC tumorigenic properties and worked in synergy with 5FU and this study thus provided preclinical evidence to support the alternative use of sitagliptin for treating CRC.

Targeting CD24/Siglec-10 signal pathway for cancer immunotherapy: recent advances and future directions.

The small, heavily glycosylated protein CD24 is primarily expressed by many immune cells and is highly expressed mostly in cancer cells. As one of the most crucial biomarkers of cancers, CD24 is frequently highly expressed in solid tumors, while tumor-associated macrophages express Siglec-10 at high levels, Siglec-10 and CD24 can interact on innate immune cells to lessen inflammatory responses to a variety of disorders. Inhibiting inflammation brought on by SHP-1 and/or SHP-2 phosphatases as well as cell phagocytosis by macrophages, the binding of CD24 to Siglec-10 can prevent toll-like receptor-mediated inflammation. Targeted immunotherapy with immune checkpoint inhibitors (ICI) has lately gained popularity as one of the best ways to treat different tumors. CD24 is a prominent innate immune checkpoint that may be a useful target for cancer immunotherapy. In recent years, numerous CD24/Siglec-10-related research studies have made tremendous progress. This study discusses the characteristics and workings of CD24/Siglec-10-targeted immunotherapy and offers a summary of current advances in CD24/Siglec-10-related immunotherapy research for cancer. We then suggested potential directions for CD24-targeted immunotherapy, basing our speculation mostly on the results of recent preclinical and clinical trials.

The Oncolytic Activity of Zika Viral Therapy in Human Neuroblastoma In Vivo Models Confers a Major Survival Advantage in a CD24-dependent Manner.

Neuroblastoma is the most common extracranial tumor, accounting for 15% of all childhood cancer-related deaths. The long-term survival of patients with high-risk tumors is less than 40%, and MYCN amplification is one of the most common indicators of poor outcomes. Zika virus (ZIKV) is a mosquito-borne flavivirus associated with mild constitutional symptoms outside the fetal period. Our published data showed that high-risk and recurrent neuroblastoma cells are permissive to ZIKV infection, resulting in cell type-specific lysis. In this study, we assessed the efficacy of ZIKV as an oncolytic treatment for high-risk neuroblastoma using in vivo tumor models. Utilizing both MYCN-amplified and non-amplified models, we demonstrated that the application of ZIKV had a rapid tumoricidal effect. This led to a nearly total loss of the tumor mass without evidence of recurrence, offering a robust survival advantage to the host. Detection of the viral NS1 protein within the tumors confirmed that a permissive infection preceded tissue necrosis. Despite robust titers within the tumor, viral shedding to the host was poor and diminished rapidly, correlating with no detectable side effects to the murine host. Assessments from both primary pretreatment and recurrent posttreatment isolates confirmed that permissive sensitivity to ZIKV killing was dependent on the expression of CD24, which was highly expressed in neuroblastomas and conferred a proliferative advantage to tumor growth. Exploiting this viral sensitivity to CD24 offers the possibility of its use as a prognostic target for a broad population of expressing cancers, many of which have shown resistance to current clinical therapies. SIGNIFICANCE: Sensitivity to the tumoricidal effect of ZIKV on high-risk neuroblastoma tumors is dependent on CD24 expression, offering a prognostic marker for this oncolytic therapy in an extensive array of CD24-expressing cancers.

The Hippo-YAP signaling pathway drives CD24-mediated immune evasion in esophageal squamous cell carcinoma via macrophage phagocytosis.

Esophageal squamous cell carcinoma (ESCC) is one of the most lethal malignancies in the world with poor prognosis. Despite the promising applications of immunotherapy, the objective response rate is still unsatisfactory. We have previously shown that Hippo/YAP signaling acts as a powerful tumor promoter in ESCC. However, whether Hippo/YAP signaling is involved in tumor immune escape in ESCC remains largely unknown. Here, we show that YAP directly activates transcription of the "don't eat me" signal CD24, and plays a crucial role in driving tumor cells to avoid phagocytosis by macrophages. Mechanistically, YAP regulates CD24 expression by interacting with TEAD and binding the CD24 promoter to initiate transcription, which facilitates tumor cell escape from macrophage-mediated immune attack. Our animal model data and clinical data show that YAP combined with CD24 in tumor microenvironment redefines the impact of TAMs on the prognosis of ESCC patients which will provide a valuable basis for precision medicine. Moreover, treatment with YAP inhibitor altered the distribution of macrophages and suppressed tumorigenesis and progression of ESCC in vivo. Together, our study provides a novel link between Hippo/YAP signaling and macrophage-mediated immune escape, which suggests that the Hippo-YAP-CD24 axis may act as a promising target to improve the prognosis of ESCC patients. A proposed model for the regulatory mechanism of Hippo-YAP-CD24-signaling axis in the tumor-associated macrophages mediated immune escape.