Antibody Treatment Research Articles

Dietary zinc deficiency promotes Acinetobacter baumannii lung infection via IL-13 in mice.

Dietary zinc deficiency is a major risk factor for pneumonia. Acinetobacter baumannii is a leading cause of ventilator-associated pneumonia and a critical public health threat due to increasing rates of multidrug resistance. Patient populations at increased risk for A. baumannii pneumonia are also at increased risk of zinc deficiency. Here we established a mouse model of dietary zinc deficiency and acute A. baumannii pneumonia to test the hypothesis that host zinc deficiency contributes to A. baumannii pathogenesis. We showed that zinc-deficient mice have significantly increased A. baumannii burdens in the lungs, dissemination to the spleen and higher mortality. During infection, zinc-deficient mice produce more pro-inflammatory cytokines, including IL-13. Administration of IL-13 promotes A. baumannii dissemination in zinc-sufficient mice, while antibody neutralization of IL-13 protects zinc-deficient mice from A. baumannii dissemination and mortality during infection. These data highlight the therapeutic potential of anti-IL-13 antibody treatments, which are well tolerated in humans, for the treatment of pneumonia.

Neutrophil swarming is crucial for limiting oral mucosal infection by Candida albicans.

Oral mucosal colonization by C. albicans (Ca) is benign in healthy people but progresses to deeper infection known as oropharyngeal candidiasis (OPC) that may become disseminated when combined with immunosuppression. Cortisone use and neutropenia are risk factors for invasive mucosal fungal infections, however the mechanisms are poorly understood. Here we identify in vivo neutrophil functional complexes known as swarms that are crucial for preventing Ca epithelial invasion. Anti-Ly6G antibody treatment impaired swarm formation and increased fungal infection depth confirming the role of neutrophil swarms in limiting Ca invasion. Neutrophil swarm function could be disrupted by administration of resolvins, and required leukotriene B4 receptor 1 (BLT1) expression so that administration of a leukotriene synthesis inhibitor reduced neutrophil swarm size permitting Ca invasion beyond the basement membrane. Cortisone treatment similarly reduced neutrophil swarming behavior and BLT1 expression and delayed expression of epithelial cytokines and chemokines. Thus, swarm structures have an important function in preventing deep invasion by C. albicans within the oral mucosa and represent a mechanism for increased disease severity under immune deficient clinical settings.

CNSC-60. SYNERGISTIC IMMUNOMODULATION THROUGH DUAL ANTIBODY THERAPY TARGETING CD47 AND CD24 FOR ENHANCED ANTITUMOR IMMUNITY IN GLIOBLASTOMA

Abstract Tumor cell phagocytosis by antigen-presenting cells (APCs) plays a pivotal role in fostering antitumor immunity. However, glioblastoma, known for its evasive strategies, exploits key phagocytosis checkpoints, including CD47, CD24, and beta-2-microglobulin. While mono-treatment targeting CD47 blockade has shown some antitumor responses in glioma, prolonged tumor-suppressing ability and significant extension of survival remain elusive. In this study, we combine anti-CD47 and anti-CD24 antibody treatments, unveiling a synergistic effect in promoting tumor cell phagocytosis. This enhanced phagocytosis profile triggers the activation of the cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) pathway in APCs, thereby facilitating efficient T cell priming. This orchestrated interplay between innate and adaptive antitumor immunity not only attenuates glioblastoma growth and extends overall survival. These findings illuminate a promising avenue for harnessing phagocytosis modulation as a strategic approach to treat challenging tumors equipped with multiple immune checkpoints.

Amyloid-beta antibody treatment in Alzheimer's disease : An update on recent data and outlook on implementation in clinical routine.

Amyloid-beta (Aβ) antibody treatment has emerged as apromising approach for the treatment of Alzheimer's disease (AD), targeting the accumulation of Aβ plaques, which are ahallmark of the disease. This review provides an update on recent clinical trial data, highlighting the efficacy and safety of various antibodies targeting Aβ. Recent trials have demonstrated that certain Aβ antibodies can reduce amyloid plaques and slow cognitive decline in patients with early AD. Key findings from trials of drugs are discussed, including their mechanisms of action, dosing regimens, and observed side effects. The potential for Aβ antibody therapy to be integrated into routine clinical practice is also explored. While Aβ antibody therapy represents asignificant advancement in AD treatment, ongoing research is needed to optimize their use and understand their long-term impact. This review underscores the importance of personalized medicine in AD and the need for continued innovation in therapeutic strategies.

Targeting Endogenous Tau in Seeded Tauopathy Models Inhibits Tau Spread.

The transmission of tau pathology has been proposed as one of the major mechanisms for the spatiotemporal spreading of tau pathology in neurodegenerative diseases. Over the last decade, studies have demonstrated that targeting total or pathological tau using tau antibodies can mitigate the development of tau pathology in tauopathy or Alzheimer's disease (AD) mouse models, and multiple tau immunotherapy agents have progressed to clinical trials. Tau antibodies are believed to inhibit the internalization of pathologic seeds and/or block seed elongation after seed internalization. To further address the mechanism of tau antibody inhibition of pathological spread, we conducted immunotherapy studies in mouse primary neurons and wild-type mice (females) seeded with AD patient-derived tau to induce the formation and spreading of tau pathology. Notably, we evaluated the effect of a mouse tau-specific antibody (mTau8) which does not interact with AD-tau seeds in these models. Our results show that mTau8 crosses the blood-brain barrier at levels similar to other antibodies and effectively decreases AD-tau-seeded tau pathology in vitro and in vivo. Importantly, our data suggest that mTau8 binds to endogenous intraneuronal mouse tau, thereby inhibiting the elongation of internalized tau seeds. These findings provide valuable insights into the possible mechanism underlying antibody-based therapies for treating tauopathies.Significance Statement The transmission of tau pathology plays key role in the pathoclinical progression of tauopathy. Studies have shown that tau antibody treatment can mitigate tau pathology in transgenic and spreading models of tauopathy. To explore the mechanisms involved in this procedure, we conducted immunotherapy studies on human tau seeds induced tau spreading models using a mouse tau-specific antibody (mTau8), which does not interact with human-tau seeds. Our findings in the study enhance our understanding of antibody-based therapies for tauopathies.

Serum CYFRA 21-1 as a Prognostic Marker in Non-Small-Cell Lung Cancer Patients Treated with Immune Checkpoint Inhibitors.

Background: A prognostic marker in patients with non-small-cell lung cancer (NSCLC) treated with anti-PD-1/PD-L1 antibodies must be established. This study explored serum cytokeratin fraction 21-1 (CYFRA 21-1), which represents a squamous cell histology, as a prognostic factor in anti-PD-1/PD-L1 antibody treatment, stratifying by histology and treatment regimen. Methods: This study retrospectively evaluated patients with advanced NSCLC without driver mutations receiving anti-PD-1/PD-L1 antibodies between November 2015 and March 2023. Cutoff values for CYFRA 21-1 and carcinoembryonic antigen (CEA) were 3.5 and 5.0 ng/mL, respectively. The Kaplan-Meier method and a log-rank test were conducted. The Cox proportional hazards model was utilized for univariate and multivariate analyses. Results: This study included 258 patients. The squamous NSCLC group demonstrated a shorter overall survival (OS) than the non-squamous NSCLC group (median, 17.8 vs. 23.7 months, p = 0.141). Patients with high serum CYFRA 21-1 and CEA levels exhibited a significantly shorter OS than those with normal levels (median, 11.7 vs. 32.7 months, p < 0.005; 15.8 vs. 29.7 months, p < 0.005). The multivariate analysis identified a performance status (PS) of ≥2, a PD-L1 expression of ≥50%, and a serum CYFRA 21-1 of >3.5 ng/mL as independent prognostic factors. Patients with high serum CYFRA 21-1 levels exhibited a significantly shorter OS even focusing on non-squamous NSCLC, anti-PD-1/PD-L1 antibody and chemotherapy combination therapy, or anti-CTLA-4 antibody combination therapy. Conclusion: Serum CYFRA 21-1 is a poor prognostic marker for patients with NSCLC receiving anti-PD-1/PD-L1 antibody treatment even when stratifying by histology or treatment regimen.

3,4,5-trimethoxycinnamic acid methyl ester isolated from Polygala tenuifolia enhances hippocampal LTP through PKA and calcium-permeable AMPA receptor

Alzheimer’s disease (AD) is a degenerative brain disorder characterized by progressive cognitive decline and neuronal death due to extracellular deposition of amyloid β (Aβ) and intracellular deposition of tau proteins. Recently approved antibody drugs targeting Aβ have been shown to slow the progression of the disease, but they have minimal effects on cognitive improvement. Therefore, there is a need to develop drugs with cognitive-enhancing effects that can be used in conjunction with these antibody treatments. In this study, we investigated whether Polygala tenuifolia (PT), traditionally known for its cognitive-enhancing effects, can improve synaptic plasticity and identified its active components and mechanisms. PT demonstrated a dose-dependent effect in enhancing long-term potentiation (LTP), and among its components, 3,4,5-trimethoxycinnamic acid methyl ester (TMCA) showed a similar LTP-enhancing effect. TMCA increased the phosphorylation of the GluA1 subunit of the α-Amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptors and increased the amount of GluA1 on the synapse without affecting the amount of GluA2. Additionally, the increase in GluA1 induced by TMCA was inhibited by a PKA inhibitor. Consistent with these results, the enhancement of LTP by TMCA was inhibited by a GluA1 antagonist and a PKA inhibitor. In silico molecular docking experiments confirmed that TMCA binds to PKA. Finally, we confirmed the LTP-enhancing effect of TMCA in hippocampal slices from 5XFAD mice. These results suggest that PT and its active component, TMCA, can interact with PKA to enhance LTP, indicating the potential for improving cognitive function in AD patients

Leveraging chemotherapy-induced PD-L1 upregulation to potentiate targeted PD-L1 degradation using nanoparticle-based targeting chimeras

The combination of nab-paclitaxel and the programmed death-ligand 1(PD-L1) antibody atezolizumab showed limited benefits in clinical trials involving PD-L1-positive triple-negative breast cancer patients. This observed lack of success is attributed to the upregulation of PD-L1 on tumor cells induced by paclitaxel, leading to resistance against PD-L1 antibodies. Here, we introduce nanoparticle-based PD-L1 targeting chimeras (NanoTACPD-L1) to induce PD-L1 degradation instead of blockade. NanoTACPD-L1 initiates endocytosis independent of specific lysosome-targeting receptors, and delivers membrane-bound PD-L1 to lysosomes for targeted degradation. Furthermore, the efficiency of degradation is directly correlated with the PD-L1 expression level. NanoTACPD-L1 effectively leverages paclitaxel-induced PD-L1 upregulation to enhance PD-L1 degradation, employing a “Meet-Plot-With-Plot” strategy. In a series of in vivo models, NanoTACPD-L1 demonstrates superior therapeutic efficacy and immune activation, both when administered individually and in combination with paclitaxel, surpassing the effects of anti-PD-L1 antibody treatment. Collectively, our study provides a nanotechnology-based tool that can be enhanced by paclitaxel for PD-L1 degradation and validates its potential application in overcoming chemo-immunotherapy resistance.

Impact of monoclonal antibody treatments on Hidradenitis Suppurativa related emergency department visits: a retrospective cohort analysis.

Impact of monoclonal antibody treatments on Hidradenitis Suppurativa related emergency department visits: a retrospective cohort analysis.

Real-world clinical results of CGRP monoclonal antibody treatment for medication overuse headache of migraine without abrupt drug discontinuation and no hospitalization

Real-world clinical results of CGRP monoclonal antibody treatment for medication overuse headache of migraine without abrupt drug discontinuation and no hospitalization

Chemogenetic activation of hepatic G12 signaling ameliorates hepatic steatosis and obesity

ObjectiveHepatic steatosis, the early stage of nonalcoholic fatty liver disease (NAFLD), currently lacks targeted pharmacological treatments. G protein-coupled receptors (GPCRs) in hepatocytes differentially regulate lipid metabolism depending on their coupling profile of G protein subtypes. Unlike Gs, Gi, and Gq signaling, the role of G12 signaling in hepatic steatosis remains elusive. The objective of this study was to investigate the effect of G12 signaling on hepatic steatosis and obesity and its mechanisms. MethodsWe generated mice expressing a G12-coupled designer GPCR in a liver-specific manner. We performed phenotypic analysis in the mice under the condition of fasting (acute hepatic steatosis model) or high-fat diet feeding (chronic hepatic steatosis model). ResultsIn acute and chronic hepatic steatosis models, chemogenetic activation of hepatic G12 signaling suppressed the progression of hepatic steatosis. The treatment led to an increased triglyceride secretion with little effect on mitochondrial respiratory activity, fatty acid oxidation, de novo lipogenesis, and fatty acid uptake. Furthermore, in a high-fat-diet-induced obesity model, activation of the G12-coupled designer GPCR exerted anti-obesity effects with increased whole-body energy expenditure and fat oxidation. Anti-FGF21 antibody treatment showed that the anti-obesity effects of the hepatic G12D activation relied in part on the hepatokine FGF21. ConclusionsOur findings indicate that the activation of G12 signaling in the liver has the potential to prevent hepatic steatosis and obesity. This discovery provides a strong rationale for the development of drugs targeting G12-coupled GPCRs expressed in the liver.

A novel antibody treatment reduces deformed wing virus loads in the western honey bee (Apis mellifera).

Deformed wing virus (DWV) is considered to be a key component of declining honey bee health which threatens global food production. The virus can result in significantly shortened lifespan, deformities in developing bees, and impaired cognition. There is currently no method to directly control the virus. The virus can be indirectly controlled with acaricidal treatments that target a key vector, the parasitic varroa mite (Varroa destructor). But acaricide resistance and a lack of effective alternatives for the control of both Varroa and DWV are major threats to beekeeping and the wider agricultural industry. Our research presents a significant development in the ability to reduce DWV burden in honey bees using IgY antibodies. Moreover, immunoglobulin Y has the potential to be more broadly established as a new treatment modality to combat other pathogens and parasites in A. mellifera.

Single-cell landscape of innate and acquired drug resistance in acute myeloid leukemia

Deep single-cell multi-omic profiling offers a promising approach to understand and overcome drug resistance in relapsed or refractory (rr) acute myeloid leukemia (AML). Here, we combine single-cell ex vivo drug profiling (pharmacoscopy) with single-cell and bulk DNA, RNA, and protein analyses, alongside clinical data from 21 rrAML patients. Unsupervised data integration reveals reduced ex vivo response to the Bcl-2 inhibitor venetoclax (VEN) in patients treated with both a hypomethylating agent (HMA) and VEN, compared to those pre-exposed to chemotherapy or HMA alone. Integrative analysis identifies both known and unreported mechanisms of innate and treatment-related VEN resistance and suggests alternative treatments, like targeting increased proliferation with the PLK inhibitor volasertib. Additionally, high CD36 expression in VEN-resistant blasts associates with sensitivity to CD36-targeted antibody treatment ex vivo. This study demonstrates how single-cell multi-omic profiling can uncover drug resistance mechanisms and treatment vulnerabilities, providing a valuable resource for future AML research.

CD14 blockade preserves left ventricular structure and systolic function in a murine model of ST-elevation myocardial infarction

Abstract Background Cluster of differentiation-14 (CD14) facilitates the excessive pro-inflammatory monocyte-macrophage response to myocardial injury. Both acute and chronic infiltration of pro-inflammatory macrophages are implicated in the immunological progression of ischemic heart failure. However, investigation of clinically practicable strategies of CD14 blockade are yet to be reported. Purpose This fully blinded and randomised preclinical study evaluated the efficacy of a neutralising anti-CD14 antibody given at reperfusion in a murine model of reperfused ST-elevation myocardial infarction (STEMI) with key clinical features. Methods Large anterior STEMI was induced in 48 adult mice by left anterior descending coronary artery occlusion for 1 h prior to reperfusion and randomisation to receive anti-CD14 antibody, isotype control (IgG2a) or saline weekly for four weeks (independently blinded). Outcome measures included functional assessments by 9.4T cardiac magnetic resonance (CMR) imaging and ultra-high-resolution echocardiography at 21- and 28-days post-STEMI, respectively. Results Multi-plane short axis CMR at 21-days post-STEMI revealed greater left ventricular (LV) ejection fraction in the anti-CD14 antibody-treated group compared with saline- and isotype-treated controls (30±1 vs 19±1 and 20±1 %, respectively, p&amp;lt;0.001; Figure 1A). CMR also revealed reduced LV dilatation with anti-CD14-treatment compared to control groups (76±5 vs 102±8 and 107±7 µl EDV in saline- and isotype-treated controls, respectively, p&amp;lt;0.05). Parasternal long axis echocardiography at 28 days post-STEMI confirmed that anti-CD14 antibody treatment was associated with greater LV systolic function compared to saline and isotype controls (30±1 vs 24±1 and 25±2 % EF, respectively, p&amp;lt;0.05; Figure 1B). Preservation of LV end-diastolic (86±4 vs 111±6 and 101±5 µl, p&amp;lt;0.01) and end-systolic (61±3 vs 84±5 and 77±5 µl, p&amp;lt;0.01) volumes was also observed with anti-CD14 treatment. Global longitudinal strain (GLS) of the LV was also significantly greater at 28 days post-STEMI with anti-CD14 treatment relative to saline and isotype controls (-8.5±0.4 vs -6.8±0.3 and -6.6±0.4 %, respectively, p&amp;lt;0.05). Conclusion(s) The findings of this fully blinded and randomised preclinical study provide evidence of a clinically practicable strategy of CD14 blockade initiated at reperfusion to mitigate progressive LV systolic dysfunction and dilatation post-STEMI.Figure 1.Functional outcome measures

Discussion of the Most Effective Scar Treatment Methods

Scars are a natural consequence of the wound healing process, but excessive scarring can lead to aesthetic and functional concerns. This paper aims to review current scar treatment methods, including modern techniques such as laser therapies, microneedling, corticosteroid injections, and silicone dressings. Special attention is given to the treatment of hypertrophic scars and keloids, which present significant challenges in contemporary medicine. An analysis of recent studies highlights the effectiveness of these methods in improving scar appearance and reducing discomfort associated with scars. Additionally, emerging experimental therapies, such as the use of stem cells and monoclonal antibody treatments, are discussed. The findings suggest that early intervention and individualized treatment approaches are crucial for achieving optimal aesthetic and functional outcomes.

Antibody blockade of the PSGL-1 immune checkpoint enhances T-cell responses to B-cell lymphoma.

Despite advancements in cancer immunotherapy, most lymphomas remain unresponsive to checkpoint inhibitors. P-selectin glycoprotein ligand-1 (PSGL-1), recently identified as a promoter of T-cell exhaustion in murine melanoma models, has emerged as a novel immune checkpoint protein and promising immunotherapeutic target. In this study, we investigated the potential of PSGL-1 antibody targeting in B-cell lymphoma. Using allogeneic co-culture systems, we demonstrated that targeted antibody interventions against human PSGL-1 enhanced T-cell activation and effector cytokine production in response to lymphoma cells. Moreover, in vitro treatment of primary lymphoma cell suspensions with PSGL-1 antibody resulted in increased activation of autologous lymphoma-infiltrating T cells. Using the A20 syngeneic B-cell lymphoma mouse model, we found that PSGL-1 antibody treatment significantly slowed tumor development and reduced the endpoint tumor burden. This antitumoral effect was accompanied by augmented tumor infiltration of CD4+ and CD8+ T cells and reduced infiltration of regulatory T cells. Finally, anti-PSGL-1 administration enhanced the expansion of CAR T cells previously transferred to mice bearing the aggressive Eμ-Myc lymphoma cells and improved disease control. These results demonstrate that PSGL-1 antibody blockade bolsters T-cell activity against B-cell lymphoma, suggesting a potential novel immunotherapeutic approach for treating these malignancies.

Monoclonal anti-amyloid antibody treatment: the epidemiological profile of the target patients in Austria and the status of treatment-eligible patients registered at an outpatient memory clinic.

The development of monoclonal anti-amyloid antibodies, adisease-modifying treatment for Alzheimer's disease (AD), has raised the necessity to identify the epidemiological profile of the possible target patients who would benefit from such therapy. These are patients in the early stages of AD with biomarker-confirmed brain amyloid positivity. In this study, the epidemiological profile of possible target patients in Austria and Vienna was estimated. The number of patients in the stage of amyloid-beta (Aβ)-positive prodromal AD in Austria and Vienna are 193,500 and 34,700 patients, respectively. The expected patient demand for the upcoming therapy in Austria and Vienna are 61,200 and 11,100 patients, respectively.In the memory clinic of the Vienna General Hospital, the number of treatment-eligible patients for an upcoming anti-amyloid antibody was on average 52.8 patients per year, which is about 10% of the total number of patients visiting the memory clinic every year. Several challenges to provide therapy to the general population include expanding the MCI screening in primary care and increasing the capacity of the healthcare system for biomarker testing, infusion delivery, and ARIA management. The study primarily addresses the status quo of identifying patients on memory clinics through cognitive screening and biomarker testing.

Real-World Experience of Erenumab in Patients with Migraine in Germany: The SPECTRE Study.

To provide real-world insights into migraine patient population in Germany treated with erenumab, focusing on the prescription patterns and reasons for the initial dosage choice. SPECTRE was an observational, non-interventional, multicenter, open-label, single-arm study in patients treated with erenumab according to approved local dose and guidelines. The study enrolled adult patients (n = 571; Germany: 105 sites) with migraine who had received erenumab for not more than 3months before the start of the study. The mean (standard deviation) patient age was 45.0 (12.3) years, and most patients were female (89.0%), Caucasian (97.6%), and non-smokers (85.1%). The starting dose of erenumab was 70mg in 68.5% of patients and 140mg in 31.5%. The proportion of patients with 140mg as the starting dose was the highest (43.5%) in those aged 30-40years. The most common reason for starting a higher dose of erenumab 140mg was severity of migraine (47.4%). During the observational period, the proportion of patients taking erenumab 140mg increased to 64.6% (visit 5; V5) after 12months. Due to attrition of patients towards the end of the study (V9: 90 participants), data at V9 must be interpreted with caution. At least one dose change was performed in 45.3% of patients (i.e., erenumab 70 to 140mg or 140 to 70mg), 21.2% of patients attempted at least once to discontinue treatment (i.e., period with erenumab discontinuation and no other antibody treatment for migraine prevention), and 15.3% discontinued erenumab treatment, mainly because of no or insufficient treatment response (13.5%). The mean time until the first omission attempt was 332.3 (range 37-633) days. Constipation (12.1%) was the most frequently reported adverse event, in line with the summary of product characteristics (SmPC) of erenumab. Most patients with migraine were prescribed erenumab 70mg as the starting dose. No new safety signals were observed for erenumab versus the previous trials.

Dynamics of tumor in situ fluid circulating tumor DNA in recurrent glioblastomas forecasts treatment efficacy of immune checkpoint blockade coupled with low-dose bevacizumab

PurposeImmune checkpoint blockade (ICB) therapies have shown efficacy in various tumors, but long-term responses in glioblastoma are less than 10%. Quantifying tumor in situ fluid circulating tumor DNA (TISF-ctDNA) and therapeutic dynamics may enable real-time GBM disease burden evaluation. This study explores the potential of tumor in situ fluid circulating tumor DNA (TISF-ctDNA) dynamics in predicting treatment efficacy.MethodsTISF and peripheral blood samples were collected from patients with recurrent glioblastoma (rGBM) undergoing tislelizumab (a programmed death 1 inhibitor) combined with low-dose bevacizumab (an anti-vascular endothelial growth factor antibody) treatment before and during each immunotherapy cycle. Biomarkers evaluated included TISF-ctDNA, measured using Next Generation Sequencing (NGS), and host inflammation markers such as the platelet-to-lymphocyte ratio (PLR).ResultsAll 32 patients received tislelizumab plus low-dose bevacizumab regularly. The median progression-free survival (PFS) was 4.0 months, and overall survival (OS) was 22.3 months. An analysis of 19 patients with continuous evaluable TISF showed baseline TISF-ctDNA abundance did not correlate with OS (p = 0.23) or PFS (p = 0.23). However, a change in TISF-ctDNA maximal Somatic Variant Allelic Frequency (MVAF) after six treatment cycles predicted both PFS (p = 0.02) and OS (p < 0.0001). Lower baseline PLR also correlated with better survival outcomes.ConclusionThe combination of tislelizumab and low-dose bevacizumab therapy appears to be effective in extending both OS and PFS in rGBM patients. Continuous TISF-ctDNA testing shows potential utility in complementing radiological monitoring. The temporal change pattern of TISF MVAF is more predictive of immunotherapy response than imaging. PLR before immunotherapy can screen patients likely to benefit from tislelizumab plus low-dose bevacizumab therapy.Trial registrationThe trial registration number: NCT05502991; Date of registration: 2022-08-14.

Tumor-intrinsic role of ICAM-1 in driving metastatic progression of triple-negative breast cancer through direct interaction with EGFR

Triple-negative breast cancer (TNBC), the most aggressive subtype, presents a critical challenge due to the absence of approved targeted therapies. Hence, there is an urgent need to identify effective therapeutic targets for this condition. While epidermal growth factor receptor (EGFR) is prominently expressed in TNBC and recognized as a therapeutic target, anti-EGFR therapies have yet to gain approval for breast cancer treatment due to their associated side effects and limited efficacy. Here, we discovered that intercellular adhesion molecule-1 (ICAM-1) exhibits elevated expression levels in metastatic breast cancer and serves as a pivotal binding adaptor for EGFR activation, playing a crucial role in malignant progression. The activation of EGFR by tumor-expressed ICAM-1 initiates biased signaling within the JAK1/STAT3 pathway, consequently driving epithelial-to-mesenchymal transition and facilitating heightened metastasis without influencing tumor growth. Remarkably, ICAM-1-neutralizing antibody treatment significantly suppressed cancer metastasis in a breast cancer orthotopic xenograft mouse model. In conclusion, our identification of ICAM-1 as a novel tumor intrinsic regulator of EGFR activation offers valuable insights for the development of TNBC-specific anti-EGFR therapies.