Search Results (1,434)

Lung cancer remains one of the most prevalent and lethal malignancies worldwide. Although conventional treatments such as surgery, chemotherapy, and radiotherapy have modestly improved patient survival, their overall efficacy remains limited, and the prognosis is generally poor. In recent years, immunotherapy, particularly immune checkpoint inhibitors, has revolutionized cancer treatment. Nevertheless, the immunosuppressive tumor microenvironment, tumor heterogeneity, and immune escape mechanisms significantly restrict the clinical benefit, which falls short of expectations. Within this context, cancer vaccines have emerged as a promising immunotherapeutic strategy. By activating the host immune system to eliminate tumor cells, cancer vaccines offer high specificity, low toxicity, and the potential to induce long-lasting immune memory. These advantages have positioned them as a focal point in cancer immunotherapy research. This paper provides a comprehensive overview of recent clinical advances in lung cancer vaccines, discusses the major challenges impeding their clinical application, and explores potential strategies to overcome these barriers. Full article

The repeated occurrence of SARS-CoV-2 variants, largely driven by virus–host interactions, was and will remain a public health concern. Spike protein mutations shaped viral infectivity, transmissibility, and immune escape. From February 2022 to April 2024, a local genomic surveillance program in Verona, Italy, was conducted on 1333 SARS-CoV-2-positive nasopharyngeal swabs via next generation full-length genome sequencing. Spike protein mutations were classified based on their prevalence over time. Mutations were grouped into five categories: fixed, emerging, fading, transient, and divergent. Notably, some divergent mutations displayed a “Lazarus effect,” disappearing and later reappearing in new lineages, indicating potential adaptive advantages in specific genomic contexts. This two-year surveillance study highlights the dynamic nature of spike protein mutations and their role in SARS-CoV-2 evolution. The findings underscore the need for ongoing mutation-focused genomic monitoring to detect early signals of variant emergence, especially among mutations previously considered disadvantageous. Such efforts are critical for driving public health responses and guiding future vaccine and therapeutic strategies. Full article

SARS-CoV-2 undergoes frequent mutations that drive viral evolution and genomic diversity, influencing transmissibility, immune escape, and disease severity. In this study, we performed whole-genome sequencing on SARS-CoV-2 isolates from patients in New York City and identified several globally rare mutations across multiple viral lineages. The isolates analyzed for rare mutations belonged to three lineages: B.1.1.7 (Alpha), B.1.526 (Iota), and B.1.623. We identified 16 rare mutations (global incidence <1000) in non-structural protein genes, including nsp2, nsp3, nsp4, nsp6, nsp8, nsp13, nsp14, ORF7a, and ORF8. Three of these mutations—located in nsp2, nsp13, and ORF8—have been reported in fewer than 100 individuals worldwide. We also detected five rare mutations in structural proteins (S, M, and N), including two—one in M and one in N—previously reported in fewer than 100 cases globally. We present clinical profiles of three patients, each infected with genetically distinct viral isolates from the three lineages studied. Furthermore, we illustrate a local transmission chain inferred from unique mutation patterns identified in the Omicron genome. These findings underscore the importance of whole-genome sequencing for detecting rare mutations, tracking community spread, and identifying emerging variants with clinical and public health significance. Full article

Conventional immunotherapy, including immune checkpoint blockade and chimeric antigen receptor (CAR)-T cells, has revolutionized cancer therapy over the past decade. Yet, the efficacy of these therapies is limited by tumor resistance, antigen escape mechanisms, poor persistence, and T-cell exhaustion, particularly in the treatment of solid tumors. The emergence of unconventional immunotherapies offers novel opportunities by leveraging diverse immune cell subsets and synthetic biologics. This review explores various immunotherapy platforms, including gamma delta T cells, invariant natural killer T cells, mucosal-associated invariant T cells, engineered regulatory T cells, and universal CAR platforms. Additionally, it expands on biologics, including bispecific and multispecific antibodies, cytokine fusions, agonists, and oncolytic viruses, showcasing their potential for modular engineering and off-the-shelf applicability. Distinct features of unconventional platforms include independence from the major histocompatibility complex (MHC), tissue-homing capabilities, stress ligand sensing, and the ability to bridge adaptive and innate immunity. Their compatibility with engineering approaches highlights their potential as scalable, efficient, and cost-effective therapies. To overcome translational challenges such as functional heterogeneity, immune exhaustion, tumor microenvironment-mediated suppression, and limited persistence, novel strategies will be discussed, including metabolic and epigenetic reprogramming, immune cloaking, gene editing, and the utilization of artificial intelligence for patient stratification. Ultimately, unconventional immunotherapies extend the therapeutic horizon of cancer immunotherapy by breaking barriers in solid tumor treatment and increasing accessibility. Continued investments in research for mechanistic insights and scalable manufacturing are key to unlocking their full clinical potential. Full article

Background/Objectives: Brain metastasis (BM) is a common and often early manifestation in lung adenocarcinoma (LUAD), yet its tumor microenvironment remains poorly defined at the time of initial diagnosis. This study aims to characterize early immune microenvironmental alterations in synchronous BM using spatial proteomic profiling. Methods: We performed digital spatial proteomic profiling using the NanoString GeoMx platform on formalin-fixed paraffin-embedded tissues from five treatment-naïve LUAD patients in whom BM was the initial presenting lesion. Paired primary lung and brain metastatic samples were analyzed across tumor and stromal compartments using 68 immune- and tumor-related protein markers. Results: Spatial profiling revealed distinct expression patterns between primary tumors and brain metastases. Immune regulatory proteins—including IDO-1, PD-1, PD-L1, STAT3, PTEN, and CD44—were significantly reduced in brain metastases (p < 0.01), whereas pS6, a marker of activation-induced T-cell death, was significantly upregulated (p < 0.01). These alterations were observed in both tumor and stromal regions, suggesting a more immunosuppressive and apoptotic microenvironment in brain lesions. Conclusions: This study provides one of the first spatially resolved proteomic characterizations of synchronous BM at initial LUAD diagnosis. Our findings highlight early immune escape mechanisms and suggest the need for site-specific immunotherapeutic strategies in patients with brain metastasis. Full article

Polyomaviruses are a family of small DNA viruses capable of establishing persistent infections, and they can pose significant pathogenic risks in immunocompromised hosts. While traditionally studied in the context of viral reactivation and immune suppression, recent evidence has highlighted the gut microbiota as a critical regulator of host immunity and viral pathogenesis. This review examines the complex interactions between polyomaviruses, the immune system, and intestinal microbiota, emphasizing the role of short-chain fatty acids (SCFAs) in modulating antiviral responses. We explore how dysbiosis may facilitate viral replication, reactivation, and immune escape and also consider how polyomavirus infection can, in turn, alter microbial composition. Particular attention is given to the Firmicutes/Bacteroidetes ratio as a potential biomarker of infection risk and immune status. Therapeutic strategies targeting the microbiota, including prebiotics, probiotics, and fecal microbiota transplantation (FMT), are discussed as innovative adjuncts to immune-based therapies. Understanding these tri-directional interactions may offer new avenues for mitigating disease severity and improving patient outcomes during viral reactivation. Full article

Early diagnosis of lung cancer is crucial for improving patient prognosis. In this study, we developed a diagnostic model for lung cancer based on serum proteomic data from the GSE168198 dataset using four machine learning algorithms (nnet, glmnet, svm, and XGBoost). The model’s performance was validated on datasets that included normal controls, disease controls, and lung cancer data containing both. Furthermore, the model’s diagnostic capability was further validated on an independent external dataset. Our analysis identified SLC16A4 as a key protein in the model, which was significantly downregulated in lung cancer serum samples compared to normal controls. The expression of SLC16A4 was closely associated with clinical pathological features such as gender, tumor stage, lymph node metastasis, and smoking history. Functional assays revealed that overexpression of SLC16A4 significantly inhibited lung cancer cell proliferation and induced cellular senescence, suggesting its potential role in lung cancer development. Additionally, correlation analyses showed that SLC16A4 expression was linked to immune cell infiltration and the expression of immune checkpoint genes, indicating its potential involvement in immune escape mechanisms. Based on multi-omics data from the TCGA database, we further discovered that the low expression of SLC16A4 in lung cancer may be regulated by DNA copy number variations and DNA methylation. In conclusion, this study not only established an efficient diagnostic model for lung cancer but also identified SLC16A4 as a promising biomarker with potential applications in early diagnosis and immunotherapy. Full article

Background: Parvovirus B19 (B19V) can cause severe relapsing episodes of pure red cell aplasia in immunocompromised individuals, which are commonly treated with intravenous immunoglobulins (IVIGs). Few data are available on B19V intra-host evolution and the role of humoral immune selection. Here, we report the dynamics of genomic mutations and subsequent protein changes during relapsing infection. Methods: Longitudinal plasma samples from immunocompromised patients with relapsing B19V infection in the period 2011–2019 were analyzed using whole-genome sequencing to evaluate intra-host evolution. The impact of mutations on the 3D viral protein structure was predicted by deep neural network modeling. Results: Of the three immunocompromised patients with relapsing infections for 3 to 9 months, one patient developed two consecutive nonsynonymous mutations in the VP1/2 region: T372S/T145S and Q422L/Q195L. The first mutation was detected in multiple B19V IgG-seropositive follow-up samples and resolved after IgG seroreversion. Computational prediction of the VP1 3D structure of this mutant showed a conformational change in the proximity of the antibody binding domain. No conformational changes were predicted for the other mutations detected. Discussion: Analysis of relapsing B19V infections showed mutational changes occurring over time. Resulting amino acid changes were predicted to lead to a conformational capsid protein change in an IgG-seropositive patient. The impact of humoral response and IVIG treatment on B19V infections should be further investigated to understand viral evolution and potential immune escape. Full article

The rapid evolution of SARS-CoV-2 has underscored the need for a detailed understanding of antibody binding mechanisms to combat immune evasion by emerging variants. In this study, we investigated the interactions between Class I neutralizing antibodies—BD55-1205, BD-604, OMI-42, P5S-1H1, and P5S-2B10—and the receptor-binding domain (RBD) of the SARS-CoV-2 spike protein using multiscale modeling, which combined molecular simulations with the ensemble-based mutational scanning of the binding interfaces and binding free energy computations. A central theme emerging from this work is that the unique binding strength and resilience to immune escape of the BD55-1205 antibody are determined by leveraging a broad epitope footprint and distributed hotspot architecture, additionally supported by backbone-mediated specific interactions, which are less sensitive to amino acid substitutions and together enable exceptional tolerance to mutational escape. In contrast, BD-604 and OMI-42 exhibit localized binding modes with strong dependence on side-chain interactions, rendering them particularly vulnerable to escape mutations at K417N, L455M, F456L and A475V. Similarly, P5S-1H1 and P5S-2B10 display intermediate behavior—effective in some contexts but increasingly susceptible to antigenic drift due to narrower epitope coverage and concentrated hotspots. Our computational predictions show strong agreement with experimental deep mutational scanning data, validating the accuracy of the models and reinforcing the value of binding hotspot mapping in predicting antibody vulnerability. This work highlights that neutralization breadth and durability are not solely dictated by epitope location, but also by how binding energy is distributed across the interface. The results provide atomistic insight into mechanisms driving resilience to immune escape for broadly neutralizing antibodies targeting the ACE2 binding interface—which stems from cumulative effects of structural diversity in binding contacts, redundancy in interaction patterns and reduced vulnerability to mutation-prone positions. Full article

In 2022, consecutive sweeps of highly transmissible SARS-CoV-2 Omicron-derived lineages (B.1.1.529*) maintained viral transmission despite extensive antigen exposure from both vaccinations and infections. To better understand Omicron variant emergence in the context of the dynamic fitness landscape of 2022, we aimed to explore putative drivers behind SARS-CoV-2 lineage replacements. Variant fitness is determined through its ability to either outrun previously dominant lineages or more efficiently circumvent host immune responses to previous infections and vaccinations. By analyzing data collected through our local genomic surveillance program from Connecticut, USA, we compared emerging Omicron lineages’ growth rates, estimated infections, effective reproductive rates, average viral copy numbers, and likelihood for causing infections in recently vaccinated individuals. We find that newly emerging Omicron lineages outcompeted dominant lineages through a combination of enhanced viral shedding or advanced immune escape depending on the population-level exposure state. This analysis integrates individual-level sequencing data with demographic, vaccination, laboratory, and epidemiological data and provides further insights into host–pathogen dynamics beyond public aggregate data. Full article

Background: Annual influenza vaccine updates target viral drift, but immune responses may be biased by original antigenic sin (OAS). Few studies have explored this across closely related strains. This study examines how OAS shapes responses to sequential influenza variants in the context of seasonal vaccination. Methods: We conducted a prospective, longitudinal study to assess the humoral immune response to the 2023–2024 seasonal influenza vaccine containing the A/Victoria/4897/2022 (H1N1) strain. Bioinformatic analyses compared the hemagglutinin (HA) sequences of A/Victoria/4897/2022 and the antigenically related A/Victoria/2570/2019 strain. B-cell epitopes were mapped with BepiPred-3.0 and BepiBlast, and their physicochemical properties analyzed via accessibility, β-turns, flexibility, and hydrophilicity. Antibody responses were measured pre- and 28 days post-Vaxigrip Tetra vaccination in young (18–35) and older (>65) adults, stratified by cytomegalovirus (CMV) serostatus. HA sequences showed >97% identity, with variations mainly in the globular head. Predicted B-cell epitopes overlapped variable sites, suggesting possible immune escape. Despite having been vaccinated against the 2022 strain, serology showed higher antibody titers against the 2019 HA strain in all participants. This pattern suggests a potential antigen imprinting effect, though confirmation awaits further analysis. Age groups differed: older adults showed greater variability, while younger CMV+ individuals tended toward stronger 2019 HA responses. Conclusions: These findings suggest a complex interplay of factors shaping immune responses, though the imprinting effect and the potential role of CMV warrant further exploration in larger, more focused studies. Full article

Background: Personalized anti-tumor therapy that activates the immune response has demonstrated clinical benefits in various cancers. However, its efficacy against testicular cancer (TC) remains uncertain. This study aims to identify suitable patients for anti-tumor immunotherapy and to uncover potential therapeutic targets in TC for the development of tailored anti-tumor immunotherapy. Methods: Consensus clustering analysis was conducted to delineate immune subtypes, while weighted gene co-expression network analysis (WGCNA), least absolute shrinkage and selection operator (LASSO) regression, and support vector machine (SVM) algorithms were employed to evaluate the potential efficacy of anti-tumor immunotherapy. Candidate immunotherapy targets were systematically identified through multi-gene panel analyses and subsequently validated using molecular biology assays. A prioritized target emerging from cellular screening was further evaluated for its capacity to potentiate anti-tumor immunity. The therapeutic efficacy of this candidate was rigorously confirmed through a comprehensive suite of immunological experiments. Results: Following systematic screening of five candidate genes (WNT11, FAM181B, GRK5, FSCN1, and ECHS1), GRK5 emerged as a promising therapeutic target for immunotherapy based on its distinct functional and molecular associations with immune evasion mechanisms. Cellular functional assays revealed that GRK5 knockdown significantly attenuated the malignant phenotype of testicular cancer cells, as evidenced by reduced proliferative capacity and invasive potential. Complementary immunological validation established that specific targeting of GRK5 with the selective antagonist GRK5-IN-2 disrupts immune evasion pathways in testicular cancer, as quantified by T-cell-mediated cytotoxicity. Conclusions: These findings position GRK5 as a critical modulator of tumor-immune escape, warranting further preclinical exploration of GRK5-IN-2 as a candidate immunotherapeutic agent. Full article

Protein functional effector (pfe)RNAs were introduced in 2015 as PIWI-interacting-like small noncoding (nc)RNAs and were later categorized as a novel group based on being 2′-O-methylated at their 3′-end, directly binding and affecting protein function, but not levels, and not matching known RNAs. Here, we document that human pfeRNAs match fragments of GenBank database-annotated human ncRNAs. PDLpfeRNAa matches the 3′-half fragment of a mitochondrial transfer (t)RNA, and PDLpfeRNAb matches a 28S ribosomal (r)RNA fragment. These PDLpfeRNAs are known to bind to tumor programmed death ligand (PD-L)1, enhancing or inhibiting its interaction with lymphocyte PD-1 and consequently tumor immune escape, respectively. In a validated 8-pfeRNA-set classifier for pulmonary nodule presence and benign vs. malignant nature, seven here match one or more of the following: transfer, micro, Y, PIWI, long (lnc)RNAs, and a PDLpfeRNAa fragment. The previously identified chromosomal locations of these pfeRNAs and their matches partially overlap. Another 2-pfeRNA set was previously determined to distinguish between controls, patients with pulmonary tuberculosis, and those with lung cancer. One pfeRNA, previously shown to bind p60-DMAD and affect apoptosis, complements small nucleolar RNA SNORD45C, matching smaller 18S rRNA and lncRNA segments. Thus, pfeRNAs appear to have a common origin with known multifunctional ncRNA fragments. Differential modification may contribute to the multifunctionality of ncRNAs. For instance, for tRNA fragments, stabilizing 3′-end 2′-O-methylation, 3′-aminoacylation, and glycosylation modifications may regulate protein function, translation, and extracellular effects, respectively. One ncRNA gene can encode multiple fragments, multiple genes can encode the same fragment, and differentially modified ncRNA fragments might synergize or antagonize each other. Full article

Liver cancer has high incidence and mortality rates worldwide, with hepatocellular carcinoma (HCC) being the main histological subtype, accounting for 90% of primary liver cancers. The high mutation rate of viruses combined with endoplasmic reticulum stress may lead to the occurrence of cancer. Hepatitis B virus (HBV) infection is one of the most important pathogenic factors of HCC. The carcinogenic mechanisms of HBV have been widely studied. Among these mechanisms, immune escape and vaccine escape caused by mutations in the HBV S gene have been reported in numerous studies of patients with chronic hepatitis B. In addition, pre-S1/S2 mutations and surface protein truncation mutations may activate multiple signaling pathways. This activation leads to the abnormal proliferation and differentiation of hepatocytes, thereby contributing to the development of HCC. This review aims to integrate the existing literature, summarize the common mutations in the HBV S gene region, and explore the related pathogenic mechanisms. Full article