Publications by authors named "Taku Kouro"

The omentum is a common site of peritoneal metastasis in various cancers, including gastric cancer. It contains immune cell aggregates known as milky spots, which provide a microenvironment for peritoneal immunity by regulating innate and adaptive immune responses. In this study, we investigated gene expression profiles in cells from omental milky spots of patients with gastric cancer (n = 37) by RNA sequencing analysis and classified the patients into four groups (G1-4).

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Neutrophil extracellular traps (NETs) released from neutrophils are related to cancer progression. However, the relationship between the therapeutic effects of immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-PD-L1 antibodies and plasma NET concentration in patients with non-small cell lung cancer (NSCLC) is poorly understood. In this study, concentrations of citrullinated histone H3 (CitH3), a surrogate marker of NETs, in plasma before/after treatment were examined in patients with advanced or recurrent NSCLC undergoing ICI treatment (n = 185).

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Background: Few studies have reported reliable prognostic factors for immune checkpoint inhibitors (ICIs) in renal cell carcinoma (RCC). Therefore, we investigated prognostic factors in patients treated with ICIs for unresectable or metastatic RCC.

Methods: We included 43 patients who received ICI treatment for RCC between January 2018 and October 2021.

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Clinical roles of plasma IL-6 levels have been reported in patients with various cancers, including non-small cell lung cancer (NSCLC), treated with immune checkpoint inhibitors (ICIs). However, the roles of other IL-6 signaling components, soluble IL-6 receptor (sIL-6R) and soluble gp130 (sgp130), in the plasma have not been elucidated. Blood was collected from 106 patients with NSCLC before initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody).

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Accurately identifying neoantigens is crucial for developing effective cancer vaccines and improving tumor immunotherapy. Mass spectrometry-based immunopeptidomics has emerged as a promising approach to identifying human leukocyte antigen (HLA) peptides presented on the surface of cancer cells, but false-positive identifications remain a significant challenge. In this study, liquid chromatography-tandem mass spectrometry-based proteomics and next-generation sequencing were utilized to identify HLA-presenting neoantigenic peptides resulting from non-synonymous single nucleotide variations in tumor tissues from 18 patients with renal cell carcinoma or pancreatic cancer.

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The selection of highly specific target antigens is critical for the development of clinically efficient and safe chimeric antigen receptors (CARs). In search of diagnostic marker for malignant mesothelioma (MM), we have established SKM9-2 monoclonal antibody (mAb) which recognizes a MM-specific molecule, sialylated Protein HEG homolog 1 (HEG1), with high specificity and sensitivity. In this study, to develop a novel therapeutic approach against MM, we generated SKM9-2 mAb-derived CARs that included the CD28 (SKM-28z) or 4-1BB (SKM-BBz) costimulatory domain.

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This study aimed to identify immune mediators, including cytokines, chemokines, and growth factors, in the plasma for predicting treatment efficacy and immune-related adverse events (irAEs) in advanced urothelial carcinoma (aUC) treated with immune checkpoint inhibitors (ICIs). We enrolled 57 patients with aUC who were treated with the anti-programmed cell death protein 1 (PD-1) antibody pembrolizumab after the failure of platinum-based chemotherapy between February 2018 and December 2020. Plasma levels of 73 soluble immune mediators were measured before and 6 weeks after initiating pembrolizumab therapy.

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Article Synopsis
  • Immune checkpoint inhibitors (ICIs) have improved survival for patients with non-small-cell lung cancer (NSCLC), but their effectiveness can vary; hence, a new machine learning tool called the Cytokine-based ICI Response Index (CIRI) was developed to enhance prediction of patient responses based on blood cytokine profiles.
  • The study involved 222 NSCLC patients, analyzing the levels of 93 cytokines before and after treatment, and utilized ensemble learning methods to identify key cytokines that could forecast overall survival (OS) for those undergoing ICI therapy.
  • The CIRI models identified specific cytokines that correlated with worse OS, achieving accurate prediction rates in independent cohorts; further advancements incorporating additional clinical data improved prediction capabilities,
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Introduction: Immune checkpoint inhibitors (ICIs) have significantly improved the prognosis of non-small cell lung cancer (NSCLC). However, only a limited proportion of patients can benefit from this therapy, and clinically useful predictive biomarkers remain to be elucidated.

Methods: Blood was collected from 189 patients with NSCLC before and six weeks after the initiation of ICI treatment (anti-PD-1 or anti-PD-L1 antibody).

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T cells play important roles in autoimmune diseases, but it remains unclear how to optimally manipulate them. We focused on the T cell immunoreceptor with Ig and ITIM domains (TIGIT), a coinhibitory molecule that regulates and is expressed in T cells. In autoimmune diseases, the association between TIGIT-expressing cells and pathogenesis and the function of human-TIGIT (hu-TIGIT) signalling modification have not been fully elucidated.

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Background: Cervical cancer is the second most common cancer in women and causes more than 250,000 deaths worldwide. Among these, the incidence of cervical adenocarcinomas is increasing. Cervical adenocarcinoma is not only difficult to detect and prevent in the early stages with screening, but it is also resistant to chemotherapy and radiotherapy, and its prognosis worsens significantly as the disease progresses.

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Chimeric antigen receptor (CAR) T cell therapy has attracted attention for its promising therapeutic effects on hematological malignancies. However, there are problems such as relapse during long-term follow-up and limited effect on solid tumors with this therapy. Exhaustion, which impairs in vivo persistence and killing activity of CAR T cells, is one of the causes of these issues.

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Article Synopsis
  • The development of effective cancer peptide vaccines relies on understanding the tumor characteristics and the immune status of each patient, especially for lung cancer.
  • Recent advancements include personalized peptide vaccines (PPVs) that select antigens based on a patient's existing immunity, showing promising results in early clinical trials.
  • There is a focus on targeting neo-antigens from genetic mutations, coupled with trials combining these vaccines with anti-PD-1 antibodies to enhance immune response against lung cancer.
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Neoantigens derived from tumor-specific genetic mutations might be suitable targets for cancer immunotherapy because of their high immunogenicity. In the current study, we evaluated the immunogenicity of 10 driver mutations that are frequently expressed in various cancers using peripheral blood mononuclear cells from healthy donors ( = 25). Of the 10 synthetic peptides (27-mer) derived from these mutations, the six peptides from KRAS-G12D, KRAS-G12R, KRAS-G13D, NRAS-Q61R, PIK3CA-H1047R, and C-Kit-D816V induced T cell responses, suggesting that frequent driver mutations are not always less immunogenic.

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B-1 cells represent a sub-fraction of B lymphocytes that participate in T cell-independent antibody production and contribute to innate immunity. While the production of B-1 cells is favored during the fetal waves of lymphopoiesis, it has been unclear when and how that differentiation option is specified. To clarify this, lymphoid and hematopoietic progenitors of fetal liver (FL) and adult bone marrow (ABM) were examined for the B cell differentiation potential.

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How hematopoietic stem cells (HSCs) produce particular lineages is insufficiently understood. We searched for key factors that direct HSC to lymphopoiesis. Comparing gene expression profiles for HSCs and early lymphoid progenitors revealed that Satb1, a global chromatin regulator, was markedly induced with lymphoid lineage specification.

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IL-5 is involved in a number of immune responses such as helminth infection and allergy. IL-5 also plays roles in innate immunity by maintaining B-1 B cells and mucosal IgA production. However, the identity of IL-5-producing cells has not been unambiguously characterized.

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IL-5 was originally defined as a T-cell-derived cytokine that triggers activated B cells for terminal differentiation into antibody-secreting plasma cells, at least in mice. Concurrently, IL-5 was recognized as the major maturation and differentiation factor for eosinophils in mice and humans. Over-expression of IL-5 significantly increases eosinophil numbers and antibody levels in vivo.

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B-1 cells are a subset of B cells responsible for the production of natural antibodies. Although the amount of natural antibody is tightly regulated, how this regulation occurs remains unknown. We examined the expression of IL-5 receptor, a cytokine receptor critical for homeostatic proliferation of B-1 cells, on B-1 cell progenitors in the fetal liver.

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Interleukin-5 (IL-5) is an interdigitating homodimeric glycoprotein that is initially identified by its ability to support the in vitro growth and differentiation of mouse B cells and eosinophils. IL-5 transgenic mouse shows two predominant features, remarkable increase in B-1 cells resulting in enhanced serum antibody levels, predominantly IgM, IgA, and IgE classes and in expansion of eosinophil numbers in the blood and eosinophil infiltration into various tissues. Conversely, mice lacking a functional gene for IL-5 or IL-5 receptor alpha chain (IL-5Ralpha) display a number of developmental and functional impairments in B cells and eosinophils.

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It has long been known that lymphopoiesis is transiently suppressed during pregnancy, which can be experimentally simulated by estrogen treatment. We now confirm with Rag1/GFP reporter mice that early lymphoid progenitors in the lineage marker(-) c-kit(high) ScaI(+), hematopoietic stem cell-enriched fraction of bone marrow are particularly depressed in these circumstances. Hematopoietic and environmental cells are both potential hormone targets and, because of this complexity, very little is known regarding mechanisms.

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The survival and fate of blood cell precursors is dependent on their communication with stromal cells of various types within bone marrow. Monoclonal antibodies have proven to be powerful tools for identifying molecules responsible for such interactions and we now describe one that selectively blocks B lymphopoiesis. The BF/32 antibody inhibited the establishment, but not the maintenance of long-term bone marrow cultures capable of lymphocyte production.

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Natural killer cells are morphologically related to and have progenitors in common with B and T lymphocytes. In this unit, protocols describe how to induce natural killer cell differentiation from prolymphocytes. Since NK cell differentiation cultures also support B cell differentiation, this protocol is extremely useful for seeking the B and NK cell branch point in their differentiation pathway.

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As well as other blood cells, B lymphocytes originate from hematopoietic stem cells. However, it is not fully understood how their production is controlled. In the serum-free, stromal-cell-free B cell differentiation culture described here, early steps of the B lineage differentiation process are reproduced under defined conditions.

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Isolation of the lymphoid progenitors in their earliest stage of development is indispensable for understanding when and how hematopoietic cell lineages are committed. Recently developed immunofluorescent labeling and sorting has made it possible to identify and isolate rare progenitors of lymphocytes. In this unit, protocols for isolating lymphoid progenitors from three different sources are provided.

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