InVivoMAb anti-mouse 4-1BB (CD137)

Cancer immunoprevention leverages the immune system's surveillance mechanisms to mitigate tumor development. Vaccines that constitute a tumor antigen and an immune adjuvant are perceived as immunoprevention modalities. However, relevant tumor antigens are unknown for non-viral cancers, which constitute most human cancers. Our group has recently shown that SA-4-1BBL, a novel agonist of CD137 receptor, but not antibodies, shows immunoprevention efficacy against various tumors. Advanced bioinformatics analyses of bulk RNA-seq data were conducted to elucidate mechanisms underlying cancer immunoprevention. Mice received subcutaneous injections of SA-4-1BBL or agonistic 3H3 antibody, and the injection-site tissue (IS) and draining lymph nodes (LN) were analyzed for differential gene expression. SA-4-1BBL induced a compartmentalized and temporally dynamic immune program characterized by early effector activation at IS and sustained immune regulation in draining LN. K-means clustering of 4564 DEGs identified eight functionally distinct clusters. IS-enriched clusters contained activation genes for CD4+ T and NK cells, including Cd28, Klra1, Cd4, Cd40, and Cd40l, while LN clusters were enriched for regulatory genes (Tnfaip3, Irf5, Col1a2) that ensure immune priming and homeostatic restraint for a balanced response. SA-4-1BBL generated a more selective and durable activation of adaptive immunity, TCR signaling, Th1/Th2 differentiation, and NK cytotoxicity. 3H3 activated broader innate inflammatory programs, including Toll-like receptor and neurodegeneration-linked pathways. IMPRes analysis showed that SA-4-1BBL activates sequential immune-regulatory circuits centered on Stat1, Cd247, and Ifng and modulates the CD151-TGF-β axis. These findings demonstrate that SA-4-1BBL elicits a balanced immune response, ensuring both safety and efficacy in preventing cancer development.

Early pregnancy loss (EPL) is closely associated with imbalances in the maternal-foetal immune microenvironment. Here we identify CD11c + CD8 + T cells, an unconventional cytotoxic T cell subset, as significantly enriched and activated in EPL cases. These cells contribute to immune dysregulation and inhibit trophoblast invasion through secreting granzyme B, perforin, CD107a, TNF-α, and IFN-γ. Furthermore, we present an effective early prediction model for EPL, based on cytokine and cytotoxic molecule profiles of CD11c + CD8 + T cells in maternal serum, collected 12-16 days post-embryo transfer. Functional assays reveal that IFN-γ triggers trophoblast pyroptosis via the NLRP3/Caspase-1/GSDMD pathway, impairing trophoblast invasion. In vivo validation using abortion-prone mice and an anti-4-1BB antibody-induced model of CD11c + CD8 + T cell activation confirms increased embryo resorption and reduced trophoblast infiltration. These findings highlight the role of dysregulated CD11c + CD8 + T cells at the maternal-foetal interface in EPL, and suggest their potential as biomarkers and therapeutic targets for EPL-management.

The SARS-CoV-2 pandemic highlighted the potential of mRNA vaccines in rapidly responding to emerging pathogens. However, immunity induced by conventional mRNA vaccines wanes quickly, requiring frequent boosters. Self-amplifying RNA (saRNA) vaccines, which extend antigen expression via self-replication, offer a promising strategy to induce more durable immune responses. In this study, we developed an saRNA vaccine encoding Zika virus (ZIKV) membrane and envelope proteins and evaluated its efficacy in mice. A single vaccination elicited strong humoral and cellular immune responses and reduced viral loads but only for 28 days. By day 84, antibody titers and T cell responses had significantly declined, resulting in reduced efficacy. To address this, we evaluated agonist antibodies targeting the T cell costimulatory molecules OX40 and 4-1BB. Coadministration of agonist antibodies enhanced CD8+ T cell responses to vaccination, resulting in sustained immunity and reduced viral loads at day 84. Depletion and passive transfer studies verified that long-term antiviral immunity was primarily CD8+ T cell dependent, with minimal contributions from antibody responses. These findings suggest that agonists targeting members of the tumor necrosis receptor superfamily, such as OX40 and 4-1BB, might enhance the durability of saRNA vaccine-induced protection, addressing a key limitation of current mRNA vaccine platforms.

T-dependent germinal center (GC) output, comprising plasma cells and memory B cells (MBCs), is crucial for clearance of Plasmodium infection and protection against reinfection. In this study, we examine the effect of an agonistic antibody targeting 4-1BB (CD137) during experimental malaria. We show that exogenous 4-1BB stimulation, despite delaying the effector GC response, surprisingly enhances humoral memory recall and protection from reinfection. Single-cell RNA and assay for transposase-accessible chromatin (ATAC) sequencing of MBCs from mice receiving 4-1BB stimulation reveal populations with distinct transcriptional signatures and a chromatin landscape indicative of superior recall and proliferative potential. Importantly, our results indicate that the effects of 4-1BB stimulation are dependent on interleukin (IL)-9R signaling in B cells but independent of parasite load during primary infection. Our study proposes an immunomodulatory approach to enhance the quality of the MBC pool, providing superior protection during infection and vaccination, particularly in the context of malaria.