Ji Eun Oh

Patients with solid cancers exhibit impaired humoral immunity, yet the underlying B cell–intrinsic mechanisms remain incompletely characterized. Here, we leveraged longitudinal SARS-CoV-2 vaccination as a model of defined antigen exposure to dissect B cell responses in cancer patients. Despite preserved early expansion following booster vaccination, cancer patients failed to sustain long-term durability and variant breadth of antigen-specific B cell responses. This defect was associated with reduced resting-memory (CD21⁺CD27⁺) and germinal center–derived (CD27⁺IgG⁺) subsets, along with a shift toward double-negative 2/3 populations. Single-cell transcriptomic and B cell receptor (BCR) repertoire analyses revealed reduced somatic hypermutation across antigen-specific B cell subsets and enrichment of a transcriptionally distinct atypical T-bet+ B cell cluster in cancer patients, collectively indicating impaired germinal center-associated maturation as a central B cell–intrinsic defect. Notably, a fourth vaccine dose restored long-term B cell maintenance, supporting proactive booster vaccination strategies for cancer patients.

Humoral immunity, mediated by B cells that mature in germinal centers in lymph nodes (LNs), is essential for adaptive immune responses, but its role in antitumor immunity and responses to immunotherapy remain unclear. Here, we show that activation of B cells in tumor-draining deep cervical LNs (dcLNs) is necessary for the efficacy of CTLA-4 (cytotoxic T lymphocyte–associated protein 4) immune checkpoint blockade in glioma in vivo. Anti–CTLA-4 therapy enhanced T follicular helper cell (T _FH cell) expansion in dcLNs, leading to germinal center B cell responses, immunoglobulin G (IgG) class switching, and the generation of glioma-reactive antibodies. Glioma-bearing mice lacking antibody-secreting cells did not benefit from CTLA-4 blockade. Distally secreted IgG accumulated in the tumor microenvironment and promoted glioma cell phagocytosis in vivo. These findings define a B cell–dependent mechanism underlying CTLA-4–mediated control of glioma and provide a conceptual framework for future therapeutic strategies in tumor.

Park J, et al. Immune Netw. 2026 Oct;26(5):e42. https://doi.org/10.4110/in.2026.26.e42

Interferon‐λ (IFN‐λ), a type III interferon that selectively targets epithelial cells, holds strong potential as an intranasal antiviral due to its ability to suppress respiratory virus replication without inducing systemic inflammation. However, clinical translation of human IFN‐λ3 (hIFN‐λ3) is hindered by limited thermostability, protease susceptibility, and rapid mucosal clearance. In this study, instability‐prone elements in hIFN‐λ3 are eliminated through artificial intelligence (AI)‐based backbone remodeling and targeted surface hydrophobic patch engineering. A protease‐sensitive loop is replaced with a de novo α‐helix, which shields neighboring hydrophobic patches and forms a new hydrophobic core, yielding an engineered variant (hIFN‐λ3‐DE1) with enhanced thermostability (Tm > 90 °C), protease resistance, and preserved antiviral activity and structural integrity even after extended heat stress (two weeks at 50 °C). Further glyco‐engineering introduces an N‐linked glycan at a site distant from receptor‐binding interfaces, improving solubility, production yield, and diffusion through synthetic nasal mucus. Intranasal administration of the resulting variant (G‐hIFN‐λ3‐DE1) enables effective mucosal penetration and provides a more rapid onset of in vivo prophylactic protection against influenza A virus. These findings highlight a robust and versatile strategy that combines AI‐driven structural design with glyco‐engineering to develop scalable, bioavailable, and functionally enhanced nasal biologics for respiratory virus prophylaxis.

Interferon-λ (IFN-λ), a type III interferon that selectively targets epithelial cells, holds strong potential as an intranasal antiviral due to its ability to suppress respiratory virus replication without inducing systemic inflammation. However, clinical translation of human IFN-λ3 (hIFN-λ3) is hindered by limited thermostability, protease susceptibility, and rapid mucosal clearance. In this study, instability-prone elements in hIFN-λ3 are eliminated through artificial intelligence (AI)-based backbone remodeling and targeted surface hydrophobic patch engineering. A protease-sensitive loop is replaced with a de novo α-helix, which shields neighboring hydrophobic patches and forms a new hydrophobic core, yielding an engineered variant (hIFN-λ3-DE1) with enhanced thermostability (Tm >90 °C), protease resistance, and preserved antiviral activity and structural integrity even after extended heat stress (two weeks at 50°C). Further glyco-engineering introduces an N-linked glycan at a site distant from receptor-binding interfaces, improving solubility, production yield, and diffusion through synthetic nasal mucus. Intranasal administration of the resulting variant (G-hIFN-λ3-DE1) enables effective mucosal penetration and provides robust prophylactic protection against influenza A virus infection in an in vivo mouse model. These findings highlight a robust and versatile strategy that combines AI-driven structural design with glyco-engineering to develop scalable, bioavailable, and functionally enhanced nasal biologics for respiratory virus prophylaxis.

Respiratory virus infections continue to pose a substantial global health challenge, requiring effective prophylactic and therapeutic strategies. Type III interferon (IFN-λ) has shown promise as an antiviral agent that strongly inhibits viral replication while minimizing systemic inflammation. Intranasal administration of IFN-λ allows easy access to the respiratory mucosa, enhancing localized antiviral responses. However, clinical application of IFN-λ is hindered by rapid mucociliary clearance, limited mucosal adhesion, and susceptibility to proteolytic degradation. Here, we develop nanoliposomes that can deliver IFN-λ through an intranasal route (NLp@IFN-λ) and act as an effective antiviral. We demonstrate that the nanoliposomes enable efficient penetration of IFN-λ in a mucus-mimicking model while allowing controlled release of the protein in vitro. NLp@IFN-λ treatment could effectively up-regulate interferon-stimulated genes in A549 cells, without inducing cytotoxicity. Finally, in vivo delivery of NLp@IFN-λ through a nasal route demonstrates prolonged retention and reduces viral load in nasal tissues in an infection model with influenza virus. This study demonstrates the potential of NLp@IFN-λ as an effective nasal delivery platform for prophylaxis of respiratory virus infections.

Representativeness of Study Participants

Representative microscopic images of paired cervical biopsies at enrollment at 6 months follow-up.