EBioMedicine最新文献

Background: Photoimmunotherapy (PIT) is a potent modality for cancer treatment. The conventional PIT regimen involves the systemic delivery of an antibody-photoabsorber conjugate, followed by a 24-h waiting period to ensure adequate localisation on the target cells. Subsequent exposure to near-infrared (NIR) light selectively damages the target cells. We aimed to improve the efficacy of PIT in vivo by evaluating the effects of the different routes of conjugate administration on treatment outcomes.

Methods: Subcutaneous Lewis lung carcinoma tumours were established in mice, targeting cluster of differentiation (CD)44 with an anti-CD44 antibody conjugated to IRDye700DX (IR700). The conjugate was administered via the intravenous or intratumoural route followed by the assessment of antibody binding and therapeutic effects of PIT.

Findings: Compared to intravenous administration, intratumoural delivery of the CD44-IR700 conjugate significantly increased the number of cells binding to the conjugate by >five-fold. This method, combined with NIR light irradiation, halved tumour growth when compared to intravenous delivery. Reducing the interval between intratumoural injection and NIR light exposure to 30 min did not diminish efficacy, thereby demonstrating the feasibility of a 1-h procedure.

Interpretation: Intratumoural administration of the antibody-photoabsorber conjugate enhanced the efficacy of PIT in vivo. A simplified, 1-h procedure involving conjugate tumour injection followed by irradiation emerged as a potent cancer treatment strategy.

Funding: This study was supported by the Japan Society for the Promotion of Science, the Japan Agency for Medical Research and Development, Japan Science and Technology Agency, and the Osaka Medical Research Foundation for Intractable Diseases.

Background: Transthoracic echocardiography (TTE) is the primary modality for diagnosing aortic stenosis (AS), yet it requires skilled operators and can be resource-intensive. We developed and validated an artificial intelligence (AI)-based system for evaluating AS that is effective in both resource-limited and advanced settings.

Methods: We created a dual-pathway AI system for AS evaluation using a nationwide echocardiographic dataset (developmental dataset, n = 8427): 1) a deep learning (DL)-based AS continuum assessment algorithm using limited 2D TTE videos, and 2) automating conventional AS evaluation. We performed internal (internal test dataset [ITDS], n = 841) and external validation (distinct hospital dataset [DHDS], n = 1696; temporally distinct dataset [TDDS], n = 772) for diagnostic value across various stages of AS and prognostic value for composite endpoints (cardiovascular death, heart failure, and aortic valve replacement).

Findings: The DL index for the AS continuum (DLi-ASc, range 0-100) increased with worsening AS severity and demonstrated excellent discrimination for any AS (AUC 0.91-0.99), significant AS (0.95-0.98), and severe AS (0.97-0.99). DLi-ASc was independent predictor for composite endpoint (adjusted hazard ratios 2.19, 1.64, and 1.61 per 10-point increase in ITDS, DHDS, and TDDS, respectively). Automatic measurement of conventional AS parameters demonstrated excellent correlation with manual measurement, resulting in high accuracy for AS staging (98.2% for ITDS, 82.1% for DHDS, and 96.8% for TDDS) and comparable prognostic value to manually-derived parameters.

Interpretation: The AI-based system provides accurate and prognostically valuable AS assessment, suitable for various clinical settings. Further validation studies are planned to confirm its effectiveness across diverse environments.

Funding: This work was supported by a grant from the Institute of Information & Communications Technology Planning & Evaluation (IITP) funded by the Korea government (Ministry of Science and ICT; MSIT, Republic of Korea) (No. 2022000972, Development of a Flexible Mobile Healthcare Software Platform Using 5G MEC); and the Medical AI Clinic Program through the National IT Industry Promotion Agency (NIPA) funded by the MSIT, Republic of Korea (Grant No.: H0904-24-1002).

Background: Immunosenescence is accelerated by chronic infectious and autoimmune diseases and could contribute to the pathobiology of multiple sclerosis (MS). How MS and disease-modifying therapies (DMTs) impact age-sensitive immune biomarkers is only partially understood.

Methods: We analyzed 771 serum samples from 147 healthy controls and 289 people with MS (PwMS) by multiplex immunoassays. We determined cytomegalovirus (CMV) serostatus and collected retrospective clinical information. We performed unsupervised and multivariable analyses.

Findings: Unsupervised analyses revealed that MS immune profile was characterized by low relative levels of anti-inflammatory/neuroprotective factors IL-4, IL-10, TNF, and β-NGF but high levels of growth factors EGF and bFGF. Serum levels of IL-4, β-NGF, IL-27, BDNF, and leptin were significantly influenced by sex and/or CMV status. IL-4 and β-NGF levels were lower in untreated PwMS compared to controls, while EGF and bFGF levels were influenced by age and markedly elevated in PwMS in multivariable analysis. Samples from treated PwMS, but not untreated PwMS, showed lower levels of BDNF and TNF than controls. Initiation of high efficacy DMTs, but not low efficacy DMTs, was associated with reduced levels of bFGF and EGF. Samples associated with distinct DMTs exhibited specific profiles for age-sensitive immune markers. Finally, lower levels of IL-6, TNF, IL-10, and β-NGF were observed at baseline in PwMS who subsequently experienced clinical failure after DMTs initiation.

Interpretation: Age, sex, CMV status, and specific DMTs significantly influence levels of age-sensitive immune biomarkers associated with MS and must be considered when investigating inflammation-related biomarkers.

Funding: This work was supported by a Grant for Multiple Sclerosis Innovation by Merck KGaA (ID: 10.12039/100009945).

Background: Neoadjuvant chemoradiotherapy (nCRT) is the standard for locally advanced rectal cancer (LARC). However, distant metastasis remains the primary cause of treatment failure. Early identification of high-risk individuals for personalized treatment may offer a solution. Circulating tumour DNA (ctDNA) could assist in this process.

Methods: From September 2017 to June 2019, the study prospectively recruited 113 patients with LARC (cT3-4N0M0 or cTanyN + M0) who underwent nCRT followed by radical surgery across 8 tertiary centers. ctDNA was analysed using large-panel targeted sequencing at baseline, during nCRT, pre-surgery, post-surgery, post-adjuvant chemotherapy (ACT), and during annual follow-ups for 3 years.

Findings: We analysed 103 tissue and 669 plasma samples from 103 patients. With a median 53-month follow-up, significantly worse progression-free survival (PFS) and overall survival (OS) were observed if median variant allele frequency (mVAF) of baseline ctDNA per patient was ≥0.5% (PFS, HR 4.39, p < 0.001; OS, HR 5.61, p = 0.004) or ctDNA was still detectable two weeks into nCRT (PFS, HR 7.63, p < 0.001; OS, HR 5.08, p < 0.001). Furthermore, when compared to the low-risk (C1) group (characterized by "ctDNA undetected during nCRT with baseline mVAF <0.5%" or "ctDNA undetected during nCRT with TMB (tumour mutational burden) ≥20/Mb"), the high-risk (C2) group (characterized by "ctDNA detected during nCRT" or "baseline mVAF ≥0.5% with TMB <20/Mb") showed significantly worse long-term outcomes (3 y-PFS, 55.9% vs. 94.2%; 3 y-OS, 79.4% vs. 100%). The ctDNA clearance during nCRT, baseline mVAF, and TMB may be effective prognostic indicators.

Interpretation: Our findings reaffirm the clinical monitoring value of ctDNA and demonstrate the strong prognostic value of baseline ctDNA and its early clearance status in patients with LARC undergoing nCRT. This highlights the potential of dynamic ctDNA monitoring as actionable stratified indicators to guide personalized neoadjuvant treatment strategies.

Funding: This work was supported by the Major Grants Program of Beijing Science and Technology Commission (No. D171100002617003) and the National High Level Hospital Clinical Research Funding (2022-PUMCH-C-005).

Background: Although antiretroviral therapy (ART) effectively inhibits viral replication, it does not fully mitigate the immunosenescence instigated by HIV infection. Cellular metabolism regulates cellular differentiation, survival, and senescence. Serine hydroxymethyltransferase 2 (SHMT2) is the first key enzyme for the entry of serine into the mitochondria from the de novo synthesis pathway that orchestrates its conversion glutathione (GSH), a key molecule in neutralising ROS and ensuring the stability of the immune system. It remains incompletely understood whether SHMT2 is involved in the senescence of CD8+ T cells, crucial for immune vigilance against HIV.

Methods: HIV-infected individuals receiving antiretroviral therapy were enrolled in our study. SHMT2-siRNA was electroporated into T cells to disrupt the gene expression of SHMT2, followed by the quantification of mRNA levels of crucial serine metabolism enzymes using real-time PCR. Immunophenotyping, proliferation, cellular and mitochondrial function, and senescence-associated signalling pathways were examined using flow cytometry in CD8+ T cell subsets.

Findings: Our findings revealed that CD8+ T cells in HIV-infected subjects are inclined towards senescence, and we identified that SHMT2, a key enzyme in serine metabolism, plays a role in CD8+ T cell senescence. SHMT2 can regulate glutathione (GSH) synthesis and protect mitochondrial function, thus effectively controlling intracellular reactive oxygen species (ROS) levels. Moreover, SHMT2 significantly contributes to averting immunosenescence and sustaining CD8+ T cell competence by modulating downstream DNA damage and phosphorylation cascades in pathways intricately linked to cellular senescence. Additionally, our study identified glycine can ameliorate CD8+ T cell senescence in HIV-infected individuals.

Interpretation: Decreased SHMT2 levels in HIV-infected CD8+ T cells affect ROS levels by altering mitochondrial function and GSH content. Increased ROS levels activate senescence-related signalling pathways in the nucleus. However, glycine supplementation counteracts these effects and moderates senescence.

Funding: This study was supported by grants from the National Key R&D Program of China (2021YFC2301900-2021YFC2301901), National Natural Science Foundation of China (82372240), and Department of Science and Technology of Liaoning Province Project for the High-Quality Scientific and Technological Development of China Medical University (2022JH2/20200074).

Background: Small cell lung cancer (SCLC) represents a highly aggressive neuroendocrine tumour with a dismal prognosis. Currently, the identification of a specific tumour antigen that can facilitate immune-based therapies for SCLC remains elusive.

Methods: We employed liquid chromatography-tandem mass spectrometry (LC-MS/MS) to analyse cancer/testis antigens (CTAs) in SCLC cell lines and human tumour specimens. Immunohistochemistry of clinical specimens was performed to compare protein expression in SCLC, non-small cell lung cancer (NSCLC), and matched normal-adjacent tissues. Additionally, publicly available RNA sequencing databases were interrogated to identify gene expression patterns in different SCLC subtypes and in different disease stages.

Findings: Distinct numbers and types of CTAs were identified across SCLC subtypes, with significantly higher expression levels of ATPase family AAA domain-containing protein 2 (ATAD2) observed in SCLC compared to normal adjacent tissues and NSCLC tissues. A dynamic expression pattern of ATAD2 was found throughout the clinical course of SCLC and exhibited a positive correlation with achaete-scute family bHLH transcription factor 1 (ASCL1) expression in SCLC. Immunopeptidomics analysis identified the YSDDDVPSV sequence derived from the HLA-A∗02:01 restriction epitope of ATAD2 as a highly promising tumour antigen candidate for potential immunotherapy applications. YSDDDVPSV immunopeptides were confirmed to be present in SCLC-A and SCLC-N with HLA-A∗02:01 restriction. Notably, HLA-A∗02:01 T cells exhibited a robust response upon stimulation with YSDDDVPSV immunopeptide pulsed by T2 cells.

Interpretation: Our findings highlight the potential of targeting the ATAD2 YSDDDVPSV immunopeptide for SCLC immunotherapy, thereby offering a promising avenue for the development of adoptive T cell therapies to effectively treat ASCL1-positive or NEUROD1-positive SCLC carrying HLA-A∗02:01.

Funding: This study was supported by the National key R&D program of China (2022YFC2505000); National Natural Science Foundation of China (NSFC) general program (82272796) NSFC special program (82241229); CAMS Innovation Fund for Medical Sciences (CIFMS 2022-I2M-1-009); CAMS Key Laboratory of Translational Research on Lung Cancer (2018PT31035); Aiyou foundation (KY201701). National key R&D program of China (2022YFC2505004). NSFC general program (81972905). Medical Oncology Key Foundation of Cancer Hospital Chinese Academy of Medical Sciences (CICAMS-MOCP2022012).

Background: The ovarian cancer (OC) preclinical detectable phase (PCDP), defined as the interval during which cancer is detectable prior to clinical diagnosis, remains poorly characterised. We report exploratory analyses from the United Kingdom Collaborative Trial of Ovarian Cancer Screening (UKCTOCS).

Methods: In UKCTOCS between Apr-2001 and Sep-2005, 101,314 postmenopausal women were randomised to no screening (NS) and 50,625 to annual multimodal screening (MMS) (until Dec-2011) using serum CA-125 interpreted by the Risk of Ovarian Cancer Algorithm (ROCA). All provided a baseline blood sample. Women with invasive epithelial OC diagnosed between randomisation and trial censorship (Dec-2014) in the MMS and NS arms with two or more CA-125 measurements, including one within two years of diagnosis were included. OC-free women (2:1 to cases) from the MMS arm provided information on baseline CA-125 distribution. CA-125 measurements were obtained from MMS results, secondary analysis of baseline samples, and medical records. PCDP duration and in-vivo tumour doubling time were estimated using the change-point model underlying ROCA. Early-stage (Stage I and II) PCDP was estimated from a Bayesian model for the probability of early stage given a CA-125 measurement.

Findings: Of 541 women (2371 CA-125 measurements) with high-grade serous cancer (HGSC), 93% (504/541) secreted CA-125 into the circulation. Median CA-125 PCDP duration for clinically-diagnosed HGSC was 15.2 (IQR 13.1-16.9, 95% IPR 9.6-21.8) months, of which 11.9 (IQR 10.5-13.1, 95% IPR 7.5-16.5) months was in early stage. The median HGSC in-vivo tumour doubling time for cancers secreting CA-125 was 2.9 (IQR 2.3-3.7, 95% IPR 1.5-7.6) months.

Interpretation: We report a comprehensive characterisation of the OC CA-125 PCDP. The 12-month window for early-stage detection and short tumour doubling time of HGSC provide a benchmark for researchers evaluating novel screening approaches including need to reduce diagnostic workup interval. Equally the findings provide urgent impetus for clinicians to reduce intervals from presentation to treatment onset.

Funding: NCI Early Detection Research Network, Concord (MA) Detect Ovarian Cancer Early Fund, MRC Clinical Trials Unit at UCL Core Funding.

Background: Lupus nephritis (LN) is one of the most common and severe complications of systemic lupus erythematosus (SLE). Multitarget therapy (MT) achieves a 20% higher complete remission (CR) rate compared to conventional therapy in LN management. Intrigued by its excellent clinical efficacy, we aimed to develop a single-agent therapy with comparable efficacy to MT, offering a simplified treatment regimen.

Methods: AZD1152, an Aurora kinase B (Aurkb) inhibitor, was identified through transcriptomic analyses and the L1000 CMap drug repurposing database. The therapeutic efficacy of AZD1152 was evaluated in MRL/lpr mice. Transcriptome sequencing and functional assays were performed to elucidate its mechanisms of action. Aurkb expression and its clinical relevance were assessed in lupus-prone mice and patients with LN.

Findings: AZD1152 significantly attenuated systemic immune activation and renal injury in MRL/lpr mice, demonstrating efficacy comparable to MT regimens in animal studies. AZD1152 treatment modulated immune-inflammatory pathways in the kidney. Aurkb expression was upregulated in T cells infiltrating the renal interstitium in LN. Additionally, Aurkb expression levels positively correlated with the activity index (AI) and serum creatinine (Scr) in patients with LN. Mechanistic studies revealed that AZD1152 exerts therapeutic effects primarily by inhibiting T-cell proliferation.

Interpretation: This study presents a drug development strategy that integrates clinically validated LN therapies with drug repurposing approaches. This strategy could accelerate drug development and clinical translation processes for LN.

Funding: A full list of funding sources can be found in the acknowledgements section.