InVivoMAb anti-mouse IFNAR-1

The proteasome inhibitor bortezomib induces apoptosis in multiple myeloma cells and has transformed patient outcome. Using in vitro as well as in vivo immunodeficient and immunocompetent murine multiple myeloma models, we here show that bortezomib also triggers immunogenic cell death (ICD), characterized by exposure of calreticulin on dying multiple myeloma cells, phagocytosis of tumor cells by dendritic cells, and induction of multiple myeloma-specific immunity. We identify a bortezomib-triggered specific ICD gene signature associated with better outcome in two independent cohorts of patients with multiple myeloma. Importantly, bortezomib stimulates multiple myeloma cell immunogenicity via activation of the cGAS/STING pathway and production of type I IFNs, and STING agonists significantly potentiate bortezomib-induced ICD. Our study therefore delineates mechanisms whereby bortezomib exerts immunotherapeutic activity and provides the framework for clinical trials of STING agonists with bortezomib to induce potent tumor-specific immunity and improve patient outcome in multiple myeloma. SIGNIFICANCE: Our study demonstrates that cGAS/STING-dependent immunostimulatory activity mediates bortezomib anti-myeloma activity in experimental models and associates with clinical response to bortezomib in patients with multiple myeloma. These findings provide the rationale for clinical evaluation of STING agonists to further potentiate anti-multiple myeloma immune response.See related commentary by Zitvogel and Kroemer. ©2021 American Association for Cancer Research.

Zika virus (ZIKV) can traverse the placental barrier, leading to fetal microcephaly and congenital zika syndrome (CZS). The viral E protein mediates host-cell interactions and infection. Here, we demonstrated that cord blood natural killer cell-derived extracellular vesicles (CBNK-EVs) potently inhibit ZIKV infection in vitro without compromising cellular viability. Mechanistically, CBNK-EVs engage ZIKV through ITGB2, a surface-enriched integrin that interacts with the viral E protein, facilitating nanoparticle-virion contact or membrane fusion. This interaction triggers antiviral activity via perforins within extracellular vesicles (EVs), resulting in diminished viral infectivity. Notably, CBNK-EVs not only effectively crossed the placental barrier to protect fetuses from ZIKV-induced pathologies, but also reduced the ZIKV burden in IFN-deficient murine models and decreased CZS incidence and mortality. Additionally, either blockade of ITGB2 with a monoclonal antibody or chelation of Ca2+ with EGTA impaired the anti-ZIKV activity of CBNK-EVs. Collectively, our findings identified CBNK-EVs as natural antiviral nanoparticles that play a pivotal role in curbing ZIKV infection and vertical transmission, offering a promising therapeutic strategy against congenital ZIKV-related complications.

Atopic diseases associated with allergens, as well as allergic diseases, frequently arise early in life; however, the age-dependent mechanisms governing immune responses to allergens remain poorly understood1. Here we find that in early life, exposure to common allergens triggers a distinct bifurcated immune response, simultaneously triggering type 17 inflammation in the skin and initiating canonical T helper 2 sensitization in the lymph nodes. This early-life γδ type 17-mediated dermatitis primes the exaggerated allergic lung inflammation upon secondary allergen exposure. Mechanistically, we find dendritic cell (DC)-mediated type 17 activation directly in the skin without requiring migration to lymph nodes; we term this state 'peripheral immune inducer' (pii) DC. CD301b+ conventional type 2 DCs acquire allergen, adopt the pii-DC state, produce IL-23 and activate local γδ type 17 cells independently of lymph-node engagement. The pii-DC state is enabled by the immature hypothalamic-pituitary-adrenal axis and physiologically low systemic glucocorticoids characteristic of early life2,3; DC-specific deletion of the glucocorticoid receptor recapitulates the pii-DC phenotype. These findings define a developmental checkpoint, set by neuroendocrine maturation, that enables in situ DC activation and immune induction, thereby shaping age-dependent responses to allergens.

Most enveloped viruses rely on furin for maturation of their surface glycoprotein. In contrast, mammarenaviruses process their glycoprotein precursor (GPC) using host site-1 protease (S1P), yet the biological implications of this unique reliance on S1P remain unclear. Here, we characterized a furin-dependent recombinant form (rCl13-RRRR) of the persistent clone 13 variant of LCMV (rCl13). Although rCl13-RRRR exhibited fitness comparable to rCl13 in cultured cells, it was highly attenuated in vivo and failed to establish persistence in immunocompetent mice. Clearance of rCl13-RRRR required interferon and CD8+ T cells, and immunization with rCl13-RRRR conferred protective immunity against a subsequent lethal LCMV challenge. Our results demonstrate that S1P-mediated processing of GPC is a key determinant of mammarenavirus fitness and immune evasion in vivo and highlight S1P as a promising and druggable target for host-directed antiviral strategies against human pathogenic mammarenaviruses.