A rise in cases of highly pathogenic avian influenza A (H5N1) clade 2.3.4.4b in humans has been reported since 2023. Although influenza seasonal vaccination (H1N1/H3N2) was shown to be effective against cases of reinfection with endemic influenza A viruses (IAVs), its capacity to elicit cross-reactive antibodies against (H5N1) remains unclear. Here, we measured vaccine-elicited antibody responses against seasonal (H1N1/H3N2) and various avian subtypes A (H5Nx) using plasma samples from the CRCHUM Health Care Workers cohort in Montreal, Canada, during the 2024 influenza seasonal vaccination. The capacity of their plasma to recognize hemagglutinin (HA) and neuraminidase (NA) antigens from ten influenza strains was measured. Their neutralizing activity, as well as their capacity to mediate antibody-dependent cellular cytotoxicity (ADCC) against cells stably expressing HA and NA, was measured. Overall, seasonal vaccination against H1N1/H3N2 elicited antibodies able to recognize several HA and NA, and in some individuals, this translated to increased neutralization and ADCC activity, including against H5Nx. This study provides insightful information on how vaccination shapes cross-reactive antibody responses against avian H5Nx.

Antibody-drug conjugates (ADCs) have profoundly reshaped the therapeutic landscape across multiple malignancies, establishing a new paradigm of targeted cytotoxic delivery. Emerging evidence indicates that the activity of ADCs extends beyond direct cytotoxicity to encompass a coordinated spectrum of immunomodulatory effects, arising from both antibody-mediated functions and payload-induced cellular stress. These mechanisms include immunogenic cell death and subsequent tumour-associated antigen release, antibody-dependent cell-mediated cytotoxicity, dendritic cell activation and tumour microenvironment reprogramming. On the basis of this biological foundation, ADCs have been increasingly explored in combination with immune checkpoint inhibitors and also with other immune-stimulating agents. Furthermore, novel ADC designs with enhanced immunological activity are emerging. In this Review, we examine the direct and indirect immunological effects underpinning the clinical activity of ADCs, appraise the clinical evidence supporting the combination of ADCs with immune checkpoint inhibitors and highlight innovative strategies to further optimize the immunogenic potential of ADCs, including antibody engineering, targeting of the tumour microenvironment, novel combinations and the use of immunostimulant payloads or bispecific antibodies. This evolving paradigm positions ADCs not merely as targeted cytotoxic agents, but rather as modulators of tumour-immune interactions, with implications for the activity of both monotherapy and combination regimens.

Monoclonal antibodies (mAbs), engineered to recognize disease-associated antigens, are central to cancer immunotherapy due to their ability to block or eliminate malignant cells by engaging immune effector mechanisms. Yet many tumors evade or suppress these responses, limiting durable clinical benefit and highlighting the need to optimize antibody-based strategies. A critical determinant of mAb activity is antibody isotype, which governs interactions with Fc receptors, complement pathways, and immune effector cells. While most approved therapeutics employ immunoglobulin G1 (IgG1) for its robust immune-stimulating capacity, evidence suggests that context-dependent isotype selection could improve efficacy. Here, we review the structural and functional properties of human IgG and IgA subclasses, with a focus on anti-CD20 rituximab in two- and three-dimensional models of human B-cell lymphoma. We further discuss how antigen density, tumor architecture, and host variables influence antibody-mediated effector functions. Together, these considerations highlight opportunities to refine antibody isotype selection for more individualized cancer immunotherapy.

Tetherin is an interferon-inducible transmembrane protein that inhibits the detachment of enveloped viruses from infected cells. HIV-1 Vpu counteracts this restriction by removing tetherin from sites of virus release. Accordingly, Vpu mutations that disrupt tetherin antagonism increase Env accumulation on the surface of HIV-infected cells. We found that Vpu mutations that impair tetherin antagonism also increase the susceptibility of HIV-infected cells to antibody-dependent cellular phagocytosis (ADCP). Increased sensitivity to ADCP was lost in tetherin-knockout cells and conditionally restored by doxycycline-inducible tetherin. Thus, Vpu protects HIV-infected cells from ADCP by preventing virion accumulation on the cell surface, similar to its protection against antibody-dependent cellular cytotoxicity (ADCC). By serving as a link between innate and adaptive immunity, the antiviral activity of tetherin may be amplified in vivo by Fc-mediated antibody effector functions and therefore much greater than initially appreciated based solely on its ability to inhibit virus release in cell culture assays.

Kidney transplantation is the optimal treatment for end-stage renal disease, yet long-term graft survival remains limited by allograft rejection. While T and B cells and donor-specific antibodies (DSA) have been the main focus, accumulating evidence indicates that natural killer (NK) cells play a significant dual role in both graft injury and immune adaptation, including in DSA-negative rejection. This narrative review summarizes current knowledge on the dual role of NK cells in kidney transplantation, with emphasis on antibody-independent mechanisms, adaptive NK-cell subsets, and their potential as biomarkers of graft outcome. NK cells are highly heterogeneous, consisting of CD56bright and CD56dimCD16 subsets. Cytomegalovirus infection promotes expansion of adaptive NKG2C+CD57+ cells with memory-like features. In rejection, NK cells act through both antibody-dependent cellular cytotoxicity and antibody-inde-pendent pathways, such as "missing-self" recognition via killer immunoglobulin-like receptors (KIR)/human leukocyte antigen (HLA) mismatch and release of the killer-specific secretory protein of 37 kDa (Ksp37). Specific NK subsets are associated with microvascular inflammation and graft loss even in the absence of DSA. In contrast, NK cells support tolerance by killing donor dendritic cells and activated T cells, producing interleukin (IL)-10 and transforming growth factor-β (TGF-β), and undergoing reeducation, gradually shifting from a cytotoxic to a regulatory phenotype. NK cells exert a dual, often opposing role in kidney transplantation, mediating both allograft injury and immune tolerance. Better understanding of their plasticity may enable new biomarkers and NK-targeted therapies to improve long-term graft survival.

Toll-like receptors (TLRs) are crucial for eliciting immune responses against pathogens such as bacteria and viruses. TLR activation has also been studied for its potential to drive antitumor activity in immune cells. TLR8 is an intracellular receptor that recognizes single-stranded RNA and promotes antiviral responses, including the release of cytokines such as TNFα and type I IFN. Previously we have shown that TLR8 activation can also modulate the expression of Fcγ receptors (FcγR), which are major drivers of antibody-mediated tumor cell clearance. Hence, TLR8 agonist treatment represents a potential means of overcoming tumor-related immunosuppression and enhancing the efficacy of antibody therapy. In chronic lymphocytic leukemia, the use of therapeutic antibodies against CD20 has become standard for treatment. However, the immune effector cells show suppressed phenotypes and weakened responses compared to their healthy-donor counterparts. Here, we investigated TLR8 agonist treatment as a means to overcome this immune suppression and enhance cellular antibody-mediated responses. Upon stimulation with the agonist TL8-506, primary CLL-patient monocytes showed an increase in the expression of activating FcγR in conjunction with reduced expression of regulatory receptors. Cytokine production was also enhanced and there was a shift in phenotypic markers, suggesting the adoption of a more M1-like state. Treatment with TLR8 agonist also elicited production of IFNγ and Granzyme B and enhanced antibody-dependent cellular cytotoxicity of antibody-coated B cells by NK cells. Agonist treatment also increased the phagocytic activity of neutrophils but did not affect the formation of neutrophil extracellular traps (NETs). Taken together, these results suggest that TLR8 agonists may help counteract the suppressed phenotypes of immune effector cells and may enhance the efficacy of antibody therapy for CLL.

IMGT[®], the international information system[®] (IMGT), was created in 1989 by Marie-Paule Lefranc (Université de Montpellier and CNRS) in Montpellier, France, to deal with and to manage the huge diversity of immunoglobulins (IG) or antibodies and T-cell receptors (TR), which are the antigen receptors (AR) of the adaptive immune response (AIR) of jawed vertebrates. The founding of IMGT[®] marked the advent of immunoinformatics, a new science which emerged at the interface between immunogenetics and bioinformatics. The biocuration of the IMGT data (IG and TR sequences, genes and structures) and the implementation of the IMGT system (7 databases, 17 tools, 25,000 Web resources pages) are based on the IMGT Scientific chart rules (keywords, labels, nomenclature, numbering…) generated from the IMGT-ONTOLOGY axioms and concepts. The IMGT nomenclature (IMGT-NC) and the IMGT unique numbering, the two pillars of immunoinformatics, have been used to define 335 engineered variants for effector properties and formats of therapeutic antibodies (including 12 chimerisotypes) and TR, fusion proteins for immune applications (FPIA) and composite proteins for clinical applications (CPCA). IMGT-NC engineered variant names from the World Health Organization (WHO) International Nonproprietary Name (INN) programme descriptions contribute to the common language for immunoinformatics and artificial intelligence (AI).

Tumor-associated neutrophils (TANs) are a highly dynamic and key component of the tumor microenvironment (TME) in solid tumors and are characterized by an exceptional degree of phenotypic plasticity and functional heterogeneity. TANs play an important role in the control of tumor evolution, metastasis, immune suppression, and therapeutic resistance. The heterogeneity of TANs is reflected in their protumor (TAN2) or antitumor (TAN1) behaviors, which depend on the signals provided by the TME, such as cytokines, metabolism, and epigenetic changes. New developments in single cell RNA sequencing and spatial transcriptomics have also revealed a range of TAN subpopulations in addition to the original TAN1/TAN2 dichotomization. Protumor TANs aid in angiogenesis, metastasis, extracellular matrix remodeling, and immunosuppression, and anti-tumor TANs play a role in cytotoxicity, antibody-dependent cellular cytotoxicity (ADCC), antigen presentation, and the promotion of adaptive immunity. This review provides a summary of the phenotypic plasticity of TANs, their dual function in solid tumors, and the underlying mechanisms. In addition, this review explains the therapeutic approaches using TANs in cancer therapy, such as blocking pro-tumor actions, reconfiguring TANs to an antitumor phenotype, restructuring the immune microenvironment, and creating novel advanced nanomedicines. This article highlights the importance of focusing on neutrophils and improving the management of solid tumors by combining their biological properties with a discussion of the possible mechanisms and limitations connected to neutrophil heterogeneity and plasticity. In addition, a fresh perspective for interpreting basic neutrophil studies in clinical practice is provided.

The acidic tumor microenvironment (pH 6.3-7.1) influences immune cell function, yet its impact on antibody-mediated killing remains poorly understood. While natural killer (NK) cells lose their spontaneous tumor-killing ability in acidic conditions, the effect on IgG-mediated killing is unexplored. Neutrophils, key effector cells in IgA immunotherapy, respond to pH changes by delayed apoptosis and show impaired bacterial killing. In this study, we investigated how extracellular acidity affects immune cell function and modulates antibody-dependent cytotoxicity by neutrophils and peripheral blood mononuclear cells (PBMCs) across multiple in vitro tumor models. Contrary to expectations, acidity significantly enhanced both IgG- and IgA-mediated tumor cell killing by neutrophils, while IgG-mediated antibody-dependent cellular cytotoxicity (ADCC) by PBMCs had a varying impact. This increased neutrophil activity was accompanied by elevated IgA-driven trogocytosis, while protumor reactive oxygen species production and neutrophil extracellular trap (NET) formation were suppressed. Cytokine profiling and Western blot analysis revealed increased Leukotriene B4 (LTB4) secretion and extracellular signal-regulated kinase (Erk) signaling, supporting enhanced neutrophil recruitment and activation in acidic conditions. Our findings reveal that, unlike other immune subsets, neutrophils maintain or even boost antibody-mediated effector functions in the acidic tumor microenvironment, providing new insight into neutrophil biology in tumors and supporting further investigation of neutrophil-targeted antibody immunotherapies.

Conserved epitopes within the coronavirus spike S2 domain elicit broadly reactive antibodies, yet many characterized responses show limited neutralizing and variable protective activity, leaving their contribution to antiviral immunity unclear. Building on our previous mapping of evolutionarily conserved spike "coldspots", we isolated human monoclonal antibodies targeting four conserved epitopes in the spike S2 domain: the internal fusion peptide (iFP), the central helix (CH), the connector domain (CD), and a membrane-proximal epitope in the heptad repeat 2 that we term the lower stalk (LS). A crystal structure of an LS-directed antibody defined a previously unresolved mode of antibody recognition of this membrane-proximal epitope, while cryogenic electron microscopy (cryo-EM) structures revealed that genetically diverse CH-specific antibodies use distinct binding modes to converge on conserved features of the prefusion S2 apex. Despite minimal neutralizing activity, CH- and LS-directed antibodies exhibited distinct antiviral functions. LS-directed antibodies mediated Fcγ receptor-dependent effector activity in vitro, whereas the broadly reactive CH-directed antibody ch.007 lacked detectable antibody-dependent cellular cytotoxicity (ADCC) or cellular phagocytosis (ADCP) activity yet protected mice from lethal SARS-CoV-2 MA10 challenge, with protection abrogated by Fcγ receptor-silencing mutations. Together, these findings expand the genetic, structural and functional landscape of human antibody responses to conserved coronavirus S2 epitopes and demonstrate that CH-directed antibodies can contribute to protective immunity through Fc-dependent mechanisms not predicted by in vitro neutralization or conventional in vitro Fc effector assays.

POU class 2 homeobox associated factor (POU2AF3) is a gene that has been associated with increased risk of colon cancer. Recently, colleagues have reported recurrent EWSR1/FUS::POU2AF3 fusions in undifferentiated spindle cell/round cell sarcomas with a predilection for the sinonasal tract. We report 11 sinonasal POU2AF3-rearranged carcinomas that are distinct from the EWSR1/FUS::POU2AF3 sarcomas. The tumors affected mostly in men (median age: 46 years) and arose in the sinonasal tract (median size: 6 cm). Clinical follow-up on 9 patients showed 6 patients developed distant metastases with a latency from the time of presentation to 16 months. Four patients died of disease, 4 were alive with disease, and 1 was alive with no evidence of disease. Most tumors showed histologic features consistent with solid adenoid cystic carcinoma (AdCC), comprising basaloid cells growing in solid nests or sheets. All showed varying extent of duct formation. Pankeratin, CK7, CD117, and CK5/6 were expressed in all tested tumors; most were also positive for S100 protein and SOX10. RNA sequencing revealed EP300::POU2AF3 (n = 6), EWSR1::POU2AF3 (n = 3), CREBBP::POU2AF3 (n = 1), and CHD7::POU2AF3 (n = 1). Most also harbored NOTCH1 mutations (6/9). MYB RNA expression was elevated by RNA sequencing and/or RNA in situ hybridization in 7/7 tested cases. Our findings support that a subset of sinonasal solid AdCC harbors POU2AF3 rearrangements, and these tumors pursue an aggressive clinical course. Diffuse expressions of pankeratin, S100 protein, SOX10, CK7, and/or CD117 provide a useful immunoprofile that reflects the diffuse overgrowth of neoplastic ductal cells in AdCC and distinguishes them from the EWSR1/FUS::POU2AF3 sarcomas.