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Dragu L. D., Chivu-Economescu M., Pitica I. M., Matei L., Bleotu C., Diaconu C. C. and Necula L. G. Targeting Exosomal PD-L1 as a New Frontier in Cancer Immunotherapy, Current issues in molecular biology, Vol 47, Issue 7, 2025, IF 3.0, doi 10.3390/cimb47070525

Abstract: Immunotherapy has emerged as a promising approach to cancer treatment, but only a small percentage of cancer patients benefit from it. To enhance therapeutic outcomes, it is essential to understand factors influencing immune response and tumor progression. Soluble PD-L1 (sPD-L1) has been identified as an essential element in immune regulation, with potential implications in cancer biology and treatment. This manuscript explores the sources and mechanisms of sPD-L1 production, its role in immune evasion and tumor progression, and its clinical significance. Elevated sPD-L1 levels have been linked to disease severity, survival, and treatment response in various malignancies, and as a consequence, strategies for combinatorial targeting of sPD-L1 with other immunotherapies are considered. Further studies are needed to understand sPD-L1 dynamics and to clarify the mechanisms of sPD-L1-mediated immunosuppression and its therapeutic implications.

Dragu L. D., Necula L. G., Bleotu C., Diaconu C. C. and Chivu-Economescu M. Soluble PD-L1: From Immune Evasion to Cancer Therapy, Life, Vol 15, Issue 4, 2025, IF 3.4, doi 10.3390/life15040626, PMID: 40283180

Neagu A. I., Bostan M , Ionescu V. A., Gheorghe G , Hotnog C. M., Roman V., Mihaila M , Stoica S. I., Diaconu C. C., Diaconu C. C., Ruta S. M. and Bleotu C. The Impact of the Microbiota on the Immune Response Modulation in Colorectal Cancer, Biomolecules, Vol 15, Issue 7,1005, 2025, IF 4.8, doi.org/10.3390/ biom15071005, PMID: 40723882

Abstract: Colorectal cancer (CRC) is a multifactorial disease increasingly recognized for its complex interplay with the gut microbiota. The disruption of microbial homeostasis—dysbiosis—has profound implications for intestinal barrier integrity and host immune function. Pathogenic bacterial species such as Fusobacterium nucleatum, Escherichia coli harbouring polyketide synthase (pks) island, and enterotoxigenic Bacteroides fragilis are implicated in CRC through mechanisms involving mucosal inflammation, epithelial barrier disruption, and immune evasion. These pathogens promote pro-tumorigenic inflammation, enhance DNA damage, and suppress effective anti-tumor immunity. Conversely, commensal and probiotic bacteria, notably Lactobacillus and Bifidobacterium species, exert protective effects by preserving epithelial barrier function and priming host immune responses. These beneficial microbes can promote the maturation of dendritic cells, stimulate CD8+ T cell cytotoxicity, and modulate regulatory T cell populations, thereby enhancing anti-tumor immunity. The dichotomous role of the microbiota underscores its potential as both a biomarker and a therapeutic target in CRC. Recent advances in studies have explored microbiota-modulating strategies—ranging from dietary interventions and prebiotics to fe- cal microbiota transplantation (FMT) and microbial consortia—as adjuncts to conventional therapies. Moreover, the composition of the gut microbiome has been shown to influence the responses to immunotherapy and chemotherapy, raising the possibility of microbiome- informed precision oncology therapy. This review synthesizes the current findings on the pathogenic and protective roles of bacteria in CRC and evaluates the translational potential of microbiome-based interventions in shaping future therapeutic paradigms.

Sandu A. M., Chifiriuc M. C., Vrancianu C. O., Cristian R.-E., Alistar C. F., Constantin M., Paun M., Alistar A., Popa L. G., Popa M. I., Tantu A. C., Sidoroff M. E., Mihai M. M., Marcu A., Popescu G., and Tantu M. M., Healthcare-Associated Infections: The Role of Microbial and Environmental Factors in Infection Control—A Narrative Review, Infectious Diseases and Therapy, Vol 14, 2025, pp. 933–971, IF ~4.6, doi: 10.1007/s40121-025-01143-0.

Abstract: Healthcare-associated infections (HAIs), previously known as nosocomial infections, represent a significant threat to healthcare systems worldwide, prolonging patient hospital stays and the duration of antimicrobial therapy. One of the most serious consequences of HAIs is the increase in the rate of antibiotic resistance (AR) generated by the prolonged, frequent, and sometimes incorrect use of antibiotics, which leads to the selection of resistant bacteria, making treatment difficult and expensive, with direct consequences for the safety of patients and healthcare personnel. Therefore, timely and accurate diagnosis of HAIs is mandatory to develop appropriate infection prevention and control practices (IPC) and new therapeutic strategies. This review aimed to present the prevalence, risk factors, current diagnosis, including artificial intelligence (AI) and machine learning approaches, future perspectives in combating HAIs causative bacteria (phage therapy, microbiome-based interventions, and vaccination), and HAIs surveillance strategies. Also, we discussed the latest findings regarding the relationships of AR with climate change and environmental pollution in the context of the One Health approach. Phage therapy is an emerging option that can offer an alternative to ineffective antibiotic treatments for antibiotic-resistant bacteria causing HAIs. Clinical trials dealing with vaccine development for resistant bacteria have yielded conflicting results. Two promising strategies, fecal microbiota transplantation and probiotic therapy, proved highly effective against recurrent Clostridium difficile infections and have been shown to reduce HAI incidence in hospitalized patients undergoing antibiotic therapy. Artificial intelligence and machine learning systems offer promising predictive capabilities in processing large volumes of clinical, microbiological, and patient data but require robust data integration. Our paper argues that HAIs are still a global challenge, requiring stringent IPC policies, computer vision, and AI-powered tools. Despite promising avenues like integrated One Health approaches, optimized phage therapy, microbiome-based interventions, and targeted vaccine development, several knowledge gaps in clinical efficacy, standardization, and pathogen complexity remain to be answered.

Chifiriuc M.C., Bleotu C. Editorial: Common themes in drug resistance: from viruses to humans, Frontiers in Microbiology, Vol. 16, 2025, IF 4.5, DOI: 10.3389/fmicb.2025.1573798.

Radu E., Fertig T.E., Dragu L.D., Pitica I.M., Surleac M., Neagu A.I., Pana L., Pais A., Matei L., Antone-Iordache I., Marta D.S., Peteu V., Nita-Lazar M., Stoica C., Popescu C., Sultana C.M., Botezatu A., Iancu I.V., Chivu-Economescu M., Banica L., Petre A.S., Paraschiv S., Gherghiceanu M., Ruta S.M., Kreuzinger N., Diaconu C.C., Bleotu C. Monitoring SARS-CoV-2 dissemination in wastewater and virus isolation in cell cultures: An integrated approach for pathogen detection and surveillance. Journal of Cellular and Molecular Medicine Sep 1 2025, 29, DOI: 10.1111/jcmm.70805

Abstract: Our study presents wastewater (WW) monitoring data, focusing on determining the infectivity of SARS-CoV-2 in the collected samples. Additionally, a panel of different viruses has been tested in the WW samples. The untreated WW monitoring campaign took place over 1 year in Bucharest, with approximately 300 samples being collected twice a week at the wastewater treatment plant (WWTP) and an infectious diseases hospital. Our data indicated that SARS-CoV-2 concentrations in WW preceded the increase in the number of clinical cases by nearly 2 weeks. Differences between locations were notable, with higher raw concentrations in WW samples from the hospital than those from the WWTP. However, after normalising to population equivalent, the hospital samples concentrations dropped significantly, suggesting that WW monitoring at the urban level provides a more complete and epidemiologically relevant picture than data obtained only from hospitals. Only a few isolates could demonstrate SARS-CoV-2 persistence during in vitro passages. Although the success rate was low, the technique remains crucial for validating the viability of viruses. Adenovirus, Bocavirus and Reovirus were the most abundant ones in both urban and hospital wastewater. WW monitoring remains the most effective approach for tracking the dissemination of various pathogens and supporting public health authorities.

Hotnog C.M., Bostan M., Anghelescu M., Roman V., Bleotu C., Hainarosie R., Voiosu C., Marineata S., Bostan I.S., Diaconu C.C., Mihaila M. Long non-coding RNAs: Significant drivers of carcinogenesis mechanisms in head and neck squamous cell carcinoma. Current Issues In Molecular Biology Aug 28 2025, 47, doi:10.3390/cimb47090698

Abstract: Head and neck squamous cell carcinoma (HNSCC) is an aggressive cancer with a complex molecular landscape. Despite extensive research, our understanding of the molecular mechanisms remains incomplete, hindering the development of effective therapeutic strategies for this disease. Long non-coding RNAs (lncRNAs) have emerged as crucial factors in cancer biology, regulating key networks across various malignancies. These molecules exert their regulatory functions through interactions with nucleic acids or proteins, thereby influencing signaling pathways within tumor cells. Consequently, lncRNAs play a significant role in key processes like cell proliferation, metastasis, immune evasion, and treatment resistance. This review offers a comprehensive overview of current knowledge regarding lncRNA-mediated mechanisms in HNSCC. The first section explores how lncRNAs influence tumor processes through various modulation mechanisms, including transcriptional and post-transcriptional regulation, chromatin remodeling, and epigenetic modifications. We also highlight the impact of lncRNAs on specific signaling pathways that control essential cellular functions (e.g., proliferation, apoptosis, angiogenesis, invasion, metastasis). Ultimately, this underscores the promising potential of lncRNAs as diagnostic biomarkers and therapeutic targets capable of enhancing patient care in oncology. Gaining a deep understanding of how lncRNAs modulate carcinogenic mechanisms may yield innovative approaches for early detection, personalized treatment, and improved clinical outcomes for HNSCC patients.

Matei L., Chivu-Economescu M., Dragu L.D., Grancea C., Bleotu C., Hrisca R., Popescu C.P., Diaconu C.C., Ruta S.M. Long-term durability and variant-specific modulation of SARS-CoV-2 humoral and cellular immunity over two years. International Journal of Molecular Sciences Aug 21 2025, 26, doi:10.3390/ijms26168106

Abstract: There is an increasing need to understand the long-term dynamics and quality of SARS-CoV-2 immune memory—both humoral and cellular—particularly with emerging variants. This study aimed to evaluate immune durability and variant-specific modulation through a longitudinal analysis of individuals with diverse SARS-CoV-2 exposure histories, over two years after infection and/or vaccination. The study involved assessing anti-spike IgG and IgA levels over time and analyzing their relationship with neutralizing activity against both ancestral and Omicron SARS-CoV-2 variants. Persistence of T cell responses was evaluated using intracellular cytokine staining (ICS) and activation-induced marker (AIM) assays. Anti-S IgG levels remained stable over time and increased after each immune stimulation, suggesting cumulative immune memory. Neutralizing capacity correlated strongly with IgG levels, showing long-term stability for pre-Omicron variants, but a moderate decline for Omicron. CD4⁺ and CD8⁺ T cell responses persisted across all groups, largely unaffected by Omicron mutations. However, cytokine profiles revealed subtle, variant-dependent changes. These findings underscore the durability of cellular immunity and the comparatively reduced robustness of Omicron-specific humoral responses. Such insights are crucial for understanding long-term protection against evolving SARS-CoV-2 variants and guiding public health strategies.

Ionescu, V.A.; Gheorghe, G.; Bleotu, C.; Puiu, L.; Mambet, C.; Diaconu, C.C.; Diaconu, C.C. Circulating miRNAs as Non-Invasive Biomarkers in Pancreatic Cancer: A Two-Phase Plasma-Based Study. J. Clin. Med. 2025, 14, 6430. https://doi.org/10.3390/jcm14186430

Abstract: Background/Objectives: MiRNAs have demonstrated promising roles in the diagnosis of pancreatic cancer and in the prognostic assessment of affected patients. Methods: We conducted a prospective pilot study including 23 patients diagnosed with advanced-stage pancreatic cancer and 10 healthy controls, matched by age and sex. In the screening phase, we evaluated the expression of 176 miRNAs in pooled plasma samples from both groups using real-time PCR. Subsequently, we validated the overexpression of selected miRNAs in individual plasma samples using the same technique. Statistical analysis was performed using IBM SPSS Statistics version 29. Results: During the screening phase, 22 miRNAs exhibited differential expression in patients with pancreatic cancer compared to healthy controls. Among these, hsa-miR-100-5p (27.8-fold increase), hsa-miR-122-5p (7.5-fold), hsa-miR-885-5p (7.2-fold), hsa-miR-34a-5p (5.7-fold), and hsa-miR-193a-5p (4.4-fold) showed the most pronounced upregulation. In the validation phase, all five candidates demonstrated significant overexpression in individual plasma samples (p < 0.001). Their circulating levels also showed associations with tumor stage (p < 0.05). Conclusions: Our findings highlight a distinct circulating miRNA signature associated with advanced pancreatic cancer, supporting the potential role of hsa-miR-100-5p, hsa-miR-122-5p, hsa-miR-885-5p, hsa-miR-34a-5p, and hsa-miR-193a-5p as minimally invasive biomarkers for disease detection and staging. Larger, multicenter studies including early-stage patients and disease control groups will be required to validate these biomarkers and determine their clinical utility.

Albulescu, A.; Fudulu, A.; Mihaila, M.A.; Iancu, I.; Plesa, A.; Bostan, M.; Botezatu, A.; Brasoveanu, L.I.; Hotnog, C.M. Epigenetic Remodeling in Thyroid Cancer: New Dimensions of Targeted Therapy Through lncRNA Modulation. Curr. Issues Mol. Biol. 2025, 47, 863. https://doi.org/10.3390/cimb47100863

Abstract: Thyroid carcinomas are phenotypically heterogeneous malignancies. Advances in molecular and cellular technologies have revealed genetic, epigenetic, and nongenetic factors underlying this heterogeneity. Our study aimed to assess the impact of single and combined treatments with anticancer agents (Carboplatin, Doxorubicin, Paclitaxel, Avastin), natural compounds (Quercetin), and epigenetic modulators (suberoylanilide hydroxamic acid and 5-Azacytidine) on the expression of long noncoding RNAs, methylation regulators, and functional features in the human thyroid cancer cell line K1. Methods: Treated and untreated K1 cells were used throughout experiments to evaluate the drug-induced cytotoxicity, apoptosis, cell cycle distribution, cytokine release, gene expression, and global DNA methylation levels. Results: Some single- and combined-drug treatments modulated both cell cycle progression and apoptotic events, demonstrating anti-tumor activity of the tested compounds. Gene expression analysis showed treatment-specific regulation of target genes and lncRNAs, including both upregulation and downregulation across different drug combinations. All treatments resulted in increased global DNA methylation levels compared to the untreated controls. Several combinations significantly upregulated DNMT1 and DNMT3B, while concomitantly decreased EZH2 levels. Conclusions: These coordinated epigenetic changes highlight the therapeutic potential of combining epigenetic modulators with chemotherapeutic agents, suggesting a strategy to prevent or reverse treatment resistance and improve outcomes in thyroid cancer patients.

Micu, A., Diaconescu, A., Minciuna, CE. et al. Overcoming the Challenge: A Comprehensive Review of Neoadjuvant Treatment Resistance in Rectal Cancer. J Gastrointest Canc 56, 205 (2025). https://doi.org/10.1007/s12029-025-01324-7

Abstract: Colorectal cancer (CRC) is the third most commonly diagnosed cancer and remains a leading cause of cancer-related mortality, particularly among younger men. Approximately one-third of colorectal cancers occur in the rectum. For patients with locally advanced rectal cancer, neoadjuvant therapy is considered the standard treatment approach. Despite advances in therapeutic approaches, improvements in the 5-year survival rate have been modest. Accurate assessment of tumor response to neoadjuvant therapy (NAT) is critical for guiding subsequent treatment strategies, especially when considering eligibility for non-operative management (NOM). Common evaluation methods include digital rectal examination (DRE), magnetic resonance imaging (MRI), and high-definition flexible endoscopy (HDFE). Tumor regression grading (TRG) systems—both histopathological (pTRG) and MRI-based (mrTRG)—are valuable tools for quantifying treatment response and predicting long-term outcomes. However, resistance to NAT remains a significant clinical challenge and is driven by a complex interplay of molecular mechanisms. Genetic factors, such as RAS mutations, have been linked to resistance to chemoradiotherapy (CRT), while tumors exhibiting microsatellite instability (MSI-high) tend to respond poorly to CRT but may show favorable outcomes with immune checkpoint inhibitors. Epigenetic pathways, including dysregulation of Wnt/β-catenin and PI3K/AKT signaling, along with alterations in DNA damage repair mechanisms, further influence CRT sensitivity. The tumor microenvironment also plays a pivotal role in modulating therapy response. Elements such as immune cell infiltration, hypoxia, angiogenesis, and the presence of cancer-associated fibroblasts (CAFs) contribute to a pro-resistance landscape. Moreover, emerging evidence suggests that gut microbiota composition—particularly an enrichment of Bacteroides species—is associated with diminished response to NAT. Understanding these multifaceted biological interactions is essential for developing personalized and more effective therapeutic strategies, with the goal of enhancing response to NAT and ultimately improving clinical outcomes in patients with rectal cancer.

Mitache, M.M., Pîndaru, A., Barbu, I.C. et al. Comprehensive evaluation of the bactericidal and anti-pathogenic efficacy of chemical disinfectants against antibiotic resistant ESKAPE clinical strains. BMC Microbiol 25, 592 (2025)

Abstract: The persistence of nosocomial pathogens in healthcare settings represents a challenge for cleaning and disinfection. Few studies have addressed the efficacy of chemical disinfectants against emergent and multidrug (MDR) resistant ESKAPE bacteria. The aim of this study was to quantify the in-use and off-label efficacy of three commercially available disinfectants: hydrogen-peroxide-, alcohol- and chlorine-based formulations — against twelve genomically characterized ESKAPE pathogens(ST101/258 Klebsiella pneumoniae, ST2 Acinetobacter baumannii, ST131/62 Escherichia coli, ST357 Pseudomonas aeruginosa, ST1 MRSA and ST612/203 vanA-positive Enterococcus faecium) plus four reference strains, and to determine how sub-lethal exposures influence key virulence traits. Disinfectant activity (log₁₀-reduction, LR) was measured by a quantitative suspension test (EN14885) with and without 3% bovine serum albumin. Additional assays simulated real-life use (contaminated nitrile/latex gloves), early biofilm formation (crystal-violet microplate assay) and evaluated the secretion of proteases, phospholipases, lipases and haemolysins. Statistical significance was assessed by one-way ANOVA or unpaired t-tests (P ≤ 0.05). All disinfectants achieved ≥ 5 LR at the manufacturer-specified concentration and contact time; however, efficacy dropped markedly when contact time was halved or concentration reduced. The hydrogen-peroxide-based disinfectant demonstrated minor differences in efficacy. Specifically, the clinical E. faecium 16 VRE strain exhibited higher MBCs compared to the reference strain (3-fold increase) (P < 0.05). A similar behavior was noticed for both clinical Pseudomonas strains that had 4-fold higher MBCs, compared to the P. aeruginosa reference strain (P < 0.05) at a 5-minute contact time. Organic soiling significantly impaired hydrogen peroxide- and chlorine-based disinfectants' activity. On artificially contaminated gloves, the label-strength alcohol-based disinfectant eradicated all strains after 60 s, whereas 30 s exposure or ≥ 25% dilution permitted recovery of up to 10⁵ CFU cm⁻². Sub-inhibitory chlorine or peroxide concentrations reduced early biofilm biomass by 40–70% (P < 0.05) and suppressed extracellular protease/phospholipase activity, while equivalent alcohol exposure had no effect. Manufacturer-recommended concentration and contact time are critical for reliable killing of MDR ESKAPE pathogens. Shortened contact or dilution—common in clinical practice—creates a survival window and may differentially select tolerant species. Chlorine and peroxide formulations additionally attenuate biofilm initiation and soluble virulence factors, suggesting a dual antimicrobial/anti-pathogenic benefit. These findings support strict compliance with label instructions and encourage formulation optimization that couples rapid killing with anti-virulence activity.

Adelina-Gabriela Niculescu, Andrei-Mihai Dumitrascu, Anıl Tevfik Koçer, Pelin Pelit Arayıcı, Selcen Arı Yuka, Sinem Koçer, Cem Bülent Üstündağ, Alexandru Mihai Grumezescu, Corneliu Ovidiu Vrancianu, Mara Madalina Mihai, Mihaela Paun, Mariana Carmen Chifiriuc. Nanotechnology-driven enhancement and modulation of immune responses in monkeypox and respiratory syncytial virus nanovaccine research. Colloids and Surfaces B: Biointerfaces, Volume 254,2025,114829,ISSN 0927-7765,https://doi.org/10.1016/j.colsurfb.2025.114829

Abstract: The global health landscape continues to face significant challenges from emerging and re-emerging viral pathogens, notably Monkeypox virus (MPXV) and Respiratory Syncytial Virus (RSV). Traditional vaccine approaches often fall short in providing robust and long-lasting immunity against these evolving threats. Nanotechnology offers transformative potential in this regard, enabling precise modulation and enhancement of immune responses through innovative nanovaccine platforms. This review delves into the latest advancements in nanotechnology-driven vaccine research targeting MPXV and RSV, focusing on the unique capabilities of nanoparticles (NPs) to optimize antigen delivery, stabilize vaccine formulations, and modulate immune responses. For MPXV, promising approaches include mRNA-lipid nanoparticles, antigen-conjugated nanoscaffolds, and virosome- or liposome-based nanovaccines, each demonstrating enhanced antigen stability and potent immunogenicity in preclinical models. RSV nanovaccine development leverages diverse nanoplatforms, such as nanocages, virus-like particles, elastin-like polypeptides, mRNA-lipid NPs, and self-aggregating lipopeptides, enabling precise antigen presentation and robust mucosal and systemic immunity. We highlight how these nanoparticle-based vaccines mimic viral structures, facilitating targeted interactions with antigen-presenting cells, optimizing antigen presentation, and promoting strong cellular and humoral immune responses. Despite these advances, clinical translation remains a challenge, with no approved MPXV or RSV nanovaccines currently available. Critical barriers include the need for further characterization of NP safety and immunogenicity, scalable manufacturing, and the identification of key viral antigens for effective targeting. This review underscores the immense potential of nanotechnology to revolutionize vaccine development against MPXV and RSV, offering insights into current challenges and future directions for the field. The integration of nanotechnology in vaccine research holds promise for more effective, durable, and accessible prophylactic solutions, addressing urgent global health needs.

Pîndaru A, Măruțescu LG, Popa M, Lambert C, Chifiriuc MC. Label-Free Flow Cytometry: A Powerful Tool to Rapidly and Accurately Assess the Efficacy of Chemical Disinfectants. Microorganisms. 2025 May 19;13(5):1156. doi: 10.3390/microorganisms13051156. PMID: 40431327; PMCID: PMC12114458

Abstract: A rapid and accurate evaluation of a chemical disinfectant’s bactericidal efficacy is crucial for ensuring effective infection control, preventing the spread of pathogens, and supporting the development of new disinfectant formulations. In this study, we report a rapid, label-free flow cytometry (FCM) protocol for evaluating the bactericidal efficacy of disinfectants. Five commercial disinfectants (alcohols, oxidizing agents, and alkylating agents) were evaluated against type strains recommended by EN 13727+A2 and ten clinical strains. The label-free FCM method allowed the determination of disinfectant efficacy through assessment of scatter light profiles (FSC-H/SSC-H) and count differences. The label-free FCM provided the results in approximately 4 h and showed strong correlation with standard tests (91.4%, sensitivity 0.94 and specificity 0.98) that can take up to 48 h. Our results represent a proof-of-principle that label-free FCM can reliably assess the efficacy of chemical disinfectants, the same day, and substantially faster than the current growth-based methods. Additionally, the study highlights the potential of the FCM method for detecting the occurrence of viable but non-culturable bacteria following treatment with chlorine-based disinfectants. With its speed, accuracy, and capability to identify bacterial injuries at a single-cell level, the FCM method is a powerful tool for assessing the efficacy of new disinfectant formulations.

Mărutescu L, Enea A, Antoniadis NM, Neculae M, Costea DA, Popa M, Dragu E, Codrici E, Ristoiu V, Galateanu B, Hudita A, Gradisteanu Pircalabioru G, Filali-Mouhim A, Vifor Gabriel Bertesteanu S, Lazăr V, Chifiriuc C, Grigore R, Ancuta P. Humoral and Cellular Immune Responses to SARS-CoV-2 in Participants with Head and Neck Cancer. Viruses. 2025 Jun 13;17(6):848. doi: 10.3390/v17060848. PMID: 40573439; PMCID: PMC12197323

Abstract: Background: SARS-CoV-2 immunity is understudied in cancer patients. Here, we monitored natural/vaccine-induced SARS-CoV-2 immunity in patients with head and neck cancer (HNC) stratified as vaccinated (mRNA/adenovirus-based vaccines), convalescent, and hybrid immunity. Methods: Plasma/PBMC samples were collected from 49 patients with HNC and 14 non-oncologic controls recruited between August 2021 and March 2022. Longitudinal follow-up was performed on 25 HNC patients. Plasma antibodies (Abs) against Spike (S1/S2), receptor-binding domain (RBD), and nucleocapsid (NC) of IgG/IgA isotypes and 25 cytokines/chemokines were quantified using MILLIPLEX® technology. The frequency, phenotype, and isotype of circulating SARS-CoV-2-specific B-cells were studied by flow cytometry using RBD tetramers (Tet++). The proliferation of B-cells and CD4+ and CD8+ T-cells in response to Spike/NC peptides was monitored by a carboxyfluorescein succinimidyl ester (CFSE) assay. Results: Plasma SARS-CoV-2 S1/S2/RBD IgG/IgA Abs were detected in all HNC participants at enrollment median time since immunization (TSI) 117 days at levels similar to controls and were significantly higher in convalescent/hybrid versus vaccinated. NC IgG/IgA Abs were only detected after infection. The frequency of Tet++ B-cells, enriched in the CD27+ memory phenotype and IgG/IgA isotype, positively correlated with plasma levels of RBD IgG/IgA Abs and Spike-specific CD4+ T-cell proliferation, regardless of the immunization status and TSI. Spike/NC-specific B-cell proliferation reached the highest levels in convalescent HNC and was positively correlated with NC IgG Abs, but not with the frequency of Tet++ B-cells. Finally, Tet++ B-cell frequencies remained stable between the two subsequent visits (median TSI: 117 versus 341 days), indicating their ability to persist for a relatively long time. Conclusions: This study monitored SARS-CoV-2 humoral/cellular immunity in an HNC cohort relative to non-oncologic participants and demonstrates that SARS-CoV-2-specific B-cells persist beyond 11 months post-immunization. These findings have implications for the management of HNC in the context of SARS-CoV-2 infection and other viral infections.

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