Khodayari, S. | bioRxiv Science

bioRxiv2026

Trans-presentation of IL-15 by IL15Rα attenuates tumor immune surveillance and is dispensable for IL-15-dependent tumor growth control

BackgroundIL-15 is a promising cytokine for cancer immunotherapy. IL-15 promotes differentiation and homeostasis of innate and adaptive immune cells, and their cytolytic effector functions. IL-15 receptor is composed of IL-15R, IL-15R{beta} and the common {gamma}c chains. IL-15 is also trans-presented as IL-15R:IL-15 complex to IL-15R{beta}:{gamma}c on neighboring cells. IL-15R is dispensable for early immune response to infections and in autoimmune diabetes. The role of IL-15R in antitumor immune responses remains unclear. MethodsIn WT, Il15-/- and Il15ra-/- mice, we studied the growth of syngeneic tumor cell lines and tumor immune surveillance against endogenous fibrosarcoma induced by methylcholanthrene (MCA). Immune gene signature and total proteome analysis were performed on MCA-induced tumors. ResultsLack of IL-15 or IL-15R did not enhance the growth of implanted tumor cell lines, despite reduced immune cell infiltration. MCA-induced tumor incidence was reduced in mice lacking IL-15R but not IL-15, although both are required for efficient tumor immunoediting. Il15-/- and Il15ra-/- tumors showed reduced Ifng expression but displayed differential modulation of Ifng-responsive genes. Proteome profiles of Il15-/- tumors, but not tumor-derived cell lines, showed significant reduction of antigen presentation pathways. B16-F10 melanoma cells expressing NLRC5, the IFN{gamma}-induced transcriptional activator of tumor antigen presentation, still required IL-15 but not IL-15R for efficient tumor control. ConclusionsOur findings show that IL-15 plays a negligible role in immunosurveillance against spontaneous tumor development, whereas IL-15R restrains immunosurveillance. Neither IL-15 nor IL-15R have a significant impact on implanted tumor models, although IL-15 facilitates efficient control of highly immunogenic tumors for which IL-15R is dispensable.

immunology↗

bioRxiv2026

Focal Neurostimulation of Calcium Signaling and Dopamine Release in Human Dopaminergic Neurons Using Megahertz-range Single-Pulse Focused Ultrasound

Focused Ultrasound (FUS) neurostimulation has increasingly attracted attention given its ability for localized targeting and non- to minimally-invasive capacity. However, the understanding of the biological and neurochemical mechanisms triggered by this neurostimulation modality remains limited. Indeed, further progress of this technology could benefit from spatiotemporal evaluation of neurotransmitter secretory activity resulting from FUS stimulation. Recently, we demonstrated in-vitro the ability of FUS to evoke calcium (Ca2+) waves, in a mixture of human neuronal and glial cells (standard cells), with single-pulse megahertz-range FUS compatible with a transdural approach relying on an intracranial FUS implant. In the present work, we investigated the ability to evoke Ca2+ signaling and dopamine (DA) release by single-pulse megahertz-range FUS stimulation of cultured human dopaminergic neurons in-vitro. A hybrid-platform integrating a custom-made FUS implant prototype (concave spherical transducer, O and focal distance: 15 mm) with real-time Ca2+ fluorescence microscopy imaging (FMI), and fast scan cyclic voltammetry (FSCV) was constructed to evaluate FUS-evoked Ca2+ signaling and concurrent DA release. Ca2+ and DA releases evoked by FUS on dopaminergic neurons (DA neurons) were compared to those evoked in standard cells. Application of single-pulse FUS (frequency: 5.11 MHz, pulse duration: 700 {micro}s, spatial average pulse average intensity, Isapa: 19.59 {+/-} 4.12 W.cm-2) was shown to causally mobilize Ca2+ dynamics in both cell types. Immediate (< 1 s) responses were focally evoked in cell clusters of 290 {micro}m in diameters; corresponding to the -3 dB FUS focal diameter. However, while standard cells exhibited continuous and omnidirectional delayed propagating dynamics following FUS stimulation, DA neurons showed more spatially sparse responses. The FUS-induced Ca2+ activity in DA neurons was accompanied by DA release detected by FSCV, but not in standard cells. This study demonstrates that single-pulse megahertz-range FUS induced with an intracranial implant prototype smaller than conventionally used FUS devices (transcranial applications) can evoke in-vitro intracellular Ca2+ activity while stimulating DA release from dopaminergic neurons, underscoring its potential as a neuro-stimulation/-modulation tool for targeting dopaminergic circuits in various pathologies.

bioengineering↗