Biology subjects

Hioki, K.

Publications and source records attributed to Hioki, K..

4 recordsLinked to original sources

bioRxiv2026

Prime-Target neoantigen vaccination unleashes unprecedented T cell immunity within ''cold'' immunosuppressive tumors

"Cold" immunosuppressive solid tumors are hard-to-treat cancers that are non-responsive to immunotherapies. Their immunosuppressive tumor microenvironment (TME) excludes and inhibits T cells and thereby hampers the therapeutic efficacy of cancer vaccines and immune checkpoint blockade. To overcome this, we employed a "Prime-Target" (P/T) neoantigen vaccination strategy that combines subcutaneous (SQ) and intra-tumor (IT) neopeptide vaccinations to first prime potent systemic neoantigen-specific T cell immunity and then trigger intratumoral T cell recruitment. Using immunotherapy non-responsive murine tumor models with pronounced immunosuppressive TMEs, we demonstrate that P/T neopeptide vaccination resulted in extraordinary tumor control and TME remodeling. P/T vaccination elicited strong systemic anti-tumor responses as well as potent and rapid recruitment of clonal CD4+ Th1 and non-exhausted CD8+ T cells into tumors that carried novel T cell receptors (TCR) and were vaccine neopeptide-specific. Concurrently, P/T vaccination reshaped the TME by decreasing suppressive Treg and M2 macrophages, and dramatically increasing the ratio of effector T cells to Treg and M2 macrophages. Vaccination-induced tumor control was neopeptide-dependent and required concurrent IT administration of both neopeptides and adjuvants. Our study highlights P/T neoantigen vaccination as a promising strategy to overcome T cell exclusion within "cold" immunosuppressive solid tumors and thereby unleash unprecedented anti-tumor immunity.

immunology↗

bioRxiv2023

5,6-dimethylxanthenone-4-acetic acid (DMXAA), a Partial STING Agonist, Competes for Human STING Activation

5,6-dimethylxanthenone-4-acetic acid (DMXAA) is a mouse-selective stimulator of interferon gene (STING) agonist exerting STING-dependent anti-tumor activity. Although DMXAA can not fully activate human STING, DMXAA reached phase III in lung cancer clinical trials. How DMXAA is effective against human lung cancer is completely unknown. Here, we show that DMXAA is a partial STING agonist interfering with agonistic STING activation, which may explain its partial anti-tumor effect observed in humans, as STING was reported to be pro-tumorigenic for lung cancer cells with low antigenicity. Furthermore, we developed a DMXAA derivative--3-hydroxy-5-(4-hydroxybenzyl)-4-methyl-9H-xhanthen-9one (HHMX)--that can potently antagonize STING-mediated immune responses both in humans and mice. Notably, HHMX suppressed aberrant responses induced by STING gain-of-function mutations causing STING-associated vasculopathy with onset in infancy (SAVI) in in vitro experiments. Furthermore, HHMX treatment suppressed aberrant STING pathway activity in peripheral blood mononuclear cells from SAVI patients. Lastly, HHMX showed a potent therapeutic effect in SAVI mouse model by mitigating disease progression. Thus, HHMX offers therapeutic potential for STING-associated autoinflammatory diseases.

immunology↗

bioRxiv2022

Reversing gut microbiome-driven adipose tissue inflammation alleviates metabolic syndrome

The gut microbiota contributes to macrophage-mediated inflammation in adipose tissue with consumption of an obesogenic diet, thus driving the development of metabolic syndrome. There is a need to identify and develop interventions that abrogate this condition. The hops-derived prenylated flavonoid xanthohumol (XN) and its semi-synthetic derivative tetrahydroxanthohumol (TXN) attenuate high-fat diet-induced obesity, hepatosteatosis and metabolic syndrome in C57Bl/6J mice. This coincides with a decrease in pro-inflammatory gene expression in the gut and adipose tissue, together with alterations in the gut microbiota and bile acid composition. In this study, we integrated and interrogated multi-omics data from different organs with fecal 16S sequences and systemic metabolic phenotypic data using a transkingdom network analysis. By incorporating cell type information from single cell RNA-seq data, we discovered TXN attenuates macrophage inflammatory processes in adipose tissue. TXN treatment also reversed levels of inflammation-inducing microbes, such as Oscillibacter valericigenes, that lead to adverse metabolic phenotypes. Furthermore, in vitro validation in macrophage cell lines and in vivo mouse supplementation showed addition of O. valericigenes supernatant induced the expression of metabolic macrophage signature genes that are downregulated by TXN in vivo. Our findings establish an important mechanism by which TXN mitigates adverse phenotypic outcomes from diet-induced obesity and metabolic syndrome. It primarily reduces the abundance of pro-inflammatory gut microbes that can otherwise promote macrophage-associated inflammation in adipose tissue.

systems biology↗

bioRxiv2021

Optimization of an LNP-mRNA vaccine candidate targeting SARS-CoV-2 receptor-binding domain

In 2020, two mRNA-based vaccines, encoding the full length of severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) spike protein, have been introduced for control of the coronavirus disease (COVID-19) pandemic1,2. However, reactogenicity, such as fever, caused by innate immune responses to the vaccine formulation remains to be improved. Here, we optimized a lipid nanoparticle (LNP)-based mRNA vaccine candidate, encoding the SARS-CoV-2 spike protein receptor-binding domain (LNP-mRNA-RBD), which showed improved immunogenicity by removing reactogenic materials from the vaccine formulation and protective potential against SARS-CoV-2 infection in cynomolgus macaques. LNP-mRNA-RBD induced robust antigen-specific B cells and follicular helper T cells in the BALB/c strain but not in the C57BL/6 strain; the two strains have contrasting abilities to induce type I interferon production by dendritic cells. Removal of reactogenic materials from original synthesized mRNA by HPLC reduced type I interferon (IFN) production by dendritic cells, which improved immunogenicity. Immunization of cynomolgus macaques with an LNP encapsulating HPLC-purified mRNA induced robust anti-RBD IgG in the plasma and in various mucosal areas, including airways, thereby conferring protection against SARS-CoV-2 infection. Therefore, fine-tuning the balance between the immunogenic and reactogenic activity of mRNA-based vaccine formulations may offer safer and more efficacious outcomes.

immunology↗