Biology subjects

Kobayashi, K. S.

Publications and source records attributed to Kobayashi, K. S..

3 recordsLinked to original sources

bioRxiv2026

A Synthetic Microbial Therapy Rewires Antitumor Immunity Across Multiple Cancer Types

Microbial immunotherapies show promise against cancer, yet broad efficacy and mechanistic insight remain elusive. Here, we introduce SPIKE 1.0 (S1.0), a metabolically engineered bacterium that converts tryptophan into immunomodulatory hydroxyindoles via tryptophan monooxygenase to remodel the tumor microenvironment (TME). A single systemic dose of S1.0 elicited potent, durable antitumor responses across multiple murine models, including humanized mice, with minimal toxicity. S1.0 enhanced inflammatory signaling, activated innate and adaptive immunity, and promoted T cell persistence, memory, and resistance to exhaustion. It outperformed checkpoint inhibitors and synergized with chemotherapy. Multi-omics profiling revealed that S1.0 rewired amino acid metabolism in tumor-infiltrating immune cells and disrupted immunosuppressive networks. These results establish S1.0 as a scalable, cost-effective microbial immunotherapy with broad translational potential for solid tumors.

immunology↗

bioRxiv2025

Identification of novel cis-acting elements, E-box and ISRE, regulating IFNγ-IRF1 axis-mediated NLRC5 expression

NLRC5 and CIITA are the primary transcriptional regulators of MHC class I and MHC class II, respectively, and play essential roles in adaptive immunity. While the regulatory mechanisms of CIITA have been extensively characterized, the transcriptional control of NLRC5 remains incompletely understood. In this study, we identified two novel conserved cis-regulatory elements within the NLRC5 promoter, an E-box and an ISRE. Furthermore, we revealed IRF1 as a novel transcriptional regulator of NLRC5, binding directly to the ISRE within the NLRC5 promoter. Using the newly identified NLRC5 ISRE, we established a screening platform to identify modulators of the IFN{gamma}-IRF1-NLRC5 axis. This system corroborated the inhibitory effects of known viral antagonists and led to the identification of novel SARS-CoV-2 viral factors that suppress IFN{gamma}- mediated IRF1 nuclear translocation, thereby inhibiting the MHC class I pathway. By elucidating the previously unproven molecular mechanism underlying IFN{gamma}-mediated NLRC5 regulation, our study provides critical insights into viral immune evasion strategies and the modulation of antigen presentation. These findings may facilitate the development of MHC class I-targeted therapeutics by modulating the IRF1-NLRC5 axis.

immunology↗

bioRxiv2022

A metabolically engineered bacterium controls autoimmunity by remodeling the pro-inflammatory microenvironment

Immunotherapy has led to impressive advances in the treatment of autoimmune and pro-inflammatory disorders; yet, its clinical outcomes remain limited by a variety of factors including the pro-inflammatory microenvironment (IME). Discovering effective immunomodulatory agents, and the mechanisms by which they control disease, will lead to innovative strategies for enhancing the effectiveness of current immunotherapeutic approaches. We have metabolically engineered an attenuated bacterial strain (i.e., Brucella melitensis 16M {Delta}vjbR, Bm{Delta}vjbR) to produce indole, a tryptophan metabolite that controls the fate and function of regulatory T cells (Tregs). We demonstrated that treatment with this strain polarized M2 macrophages (M{varphi}) which produced anti-inflammatory cytokines (e.g., IL-10) and promoted Treg function; moreover, when combined with adoptive cell transfer (ACT) of Tregs, a single treatment with our engineered bacterial strain dramatically reduced the incidence and score of autoimmune arthritis and decreased joint damage. These findings show how a metabolically engineered bacterium can constitute a powerful vehicle for improving the efficacy of immunotherapy, defeating autoimmunity and reducing inflammation by remodeling the IME and augmenting Treg function.

immunology↗