Tumor epitope spreading by a novel multivalent therapeutic cellular vaccine targeting cancer antigens to invariant NKT-triggered dendritic cells in situ

IntroductionCancer is categorized into two types based on the microenvironment: cold and hot tumors. The former is challenging to stimulate through immunity. The immunogenicity of cancer relies on the quality and quantity of cancer antigens, whether recognized by T cells or not. Successful cancer immunotherapy hinges on the cancer cell type, antigenicity and subsequent immune reactions. The T cell response is particularly crucial for secondary epitope spreading, although the factors affecting these mechanisms remain unknown. Prostate cancer often becomes resistant to standard therapy despite identifying several antigens, placing it among immunologically cold tumors. We aim to leverage prostate cancer antigens to investigate the potential induction of epitope spreading in cold tumors. This study specifically focuses on identifying factors involved in secondary epitope spreading based on artificial adjuvant vector cell (aAVC) therapy, a method established as invariant natural killer T (iNKT) -licensed DC therapy.MethodsWe concentrated on three prostate cancer antigens (prostate-specific membrane antigen (PSMA), prostate-specific antigen (PSA), and prostatic acid phosphatase (PAP)). By introducing allogeneic cells with the antigen and murine CD1d mRNA, followed by α-galactosylceramide (α-GalCer) loading, we generated five types of aAVCs, i.e, monovalent, divalent and trivalent antigen-expressing aAVCs and four types of prostate antigen-expressing cold tumors. We evaluated iNKT activation and antigen-specific CD8+ T cell responses against tumor cells prompted by the aAVCs.ResultsOur study revealed that monovalent aAVCs, expressing a single prostate antigen, primed T cells for primary tumor antigens and also induced T cells targeting additional tumor antigens by triggering a tumor antigen-spreading response. When we investigated the immune response by trivalent aAVC (aAVC-PROS), aAVC-PROS therapy elicited multiple antigen-specific CD8+ T cells simultaneously. These CD8+ T cells exhibited both preventive and therapeutic effects against tumor progression.ConclusionsThe findings from this study highlight the promising role of tumor antigen-expressing aAVCs, in inducing efficient epitope spreading and generating robust immune responses against cancer. Our results also propose that multivalent antigen-expressing aAVCs present a promising therapeutic option and could be a more comprehensive therapy for treating cold tumors like prostate cancer

Activation of Natural Killer T Cells by α-Galactosylceramide Rapidly Induces the Full Maturation of Dendritic Cells In Vivo and Thereby Acts as an Adjuvant for Combined CD4 and CD8 T Cell Immunity to a Coadministered Protein

The maturation of dendritic cells (DCs) allows these antigen-presenting cells to initiate immunity. We pursued this concept in situ by studying the adjuvant action of α-galactosylceramide (αGalCer) in mice. A single i.v. injection of glycolipid induced the full maturation of splenic DCs, beginning within 4 h. Maturation was manifest by marked increases in costimulator and major histocompatibility complex class II expression, interferon (IFN)-γ production, and stimulation of the mixed leukocyte reaction. These changes were not induced directly by αGalCer but required natural killer T (NKT) cells acting independently of the MyD88 adaptor protein. To establish that DC maturation was responsible for the adjuvant role of αGalCer, mice were given αGalCer together with soluble or cell-associated ovalbumin antigen. Th1 type CD4+ and CD8+ T cell responses developed, and the mice became resistant to challenge with ovalbumin-expressing tumor. DCs from mice given ovalbumin plus adjuvant, but not the non-DCs, stimulated ovalbumin-specific proliferative responses and importantly, induced antigen-specific, IFN-γ producing, CD4+ and CD8+ T cells upon transfer into naive animals. In the latter instance, immune priming did not require further exposure to ovalbumin, αGalCer, NKT, or NK cells. Therefore a single dose of αGalCer i.v. rapidly stimulates the full maturation of DCs in situ, and this accounts for the induction of combined Th1 CD4+ and CD8+ T cell immunity to a coadministered protein

Pollution by estrogens in river and estuarine waters around Kuala Lumpur, Malaysia, and their effects on the estuarine Java-medaka, Oryzias javanicus.

Estrogens (17 B-estradiol and estrone) concentrations in river and estuarine waters around Kuala Lumpur, Malaysia were determined by enzyme-linked immunosorbent assay while estrogenic potential of the waters were ascertained by three in vitro bioassays, namely E-screen, Ishikawa cell-alkaline phosphatase and yeast estrogen screen. Moreover, hepatic vitellogenin, a precursor of yolk protein that is specific to females, were examined in male and female Java-medaka collected in the same area. 17B-estradiol and estrone concentrations were less than 6.1 ng/L and 127 ng/L, respectively. The highest 17B-estradiol equivalent activity, 284 ng/L, was detected by in vitro assay in Sungai Kuyoh, which was adjacent to a sewage plant. 17B-estradiol and estrone concentrations were not equal to their estrogenic potentials determined by in vitro assay implying the presence of other estrogenic chemicals in these waters. Hepatic vitellogenin concentrations of both male and female java-medaka were the same to laboratory-cultured individuals. Although relatively high estrogen concentrations were detected in some waters of Malaysia, these were not high enough to induce hepatic vitellogenin in male fishes. Further research, however, is necessary to cover more number of sampling sites

The Linkage of Innate to Adaptive Immunity via Maturing Dendritic Cells In Vivo Requires CD40 Ligation in Addition to Antigen Presentation and CD80/86 Costimulation

Dendritic cell (DC) maturation is an innate response that leads to adaptive immunity to coadministered proteins. To begin to identify underlying mechanisms in intact lymphoid tissues, we studied α-galactosylceramide. This glycolipid activates innate Vα14+ natural killer T cell (NKT) lymphocytes, which drive DC maturation and T cell responses to ovalbumin antigen. Hours after giving glycolipid i.v., tumor necrosis factor (TNF)–α and interferon (IFN)-γ were released primarily by DCs. These cytokines induced rapid surface remodeling of DCs, including increased CD80/86 costimulatory molecules. Surprisingly, DCs from CD40−/− and CD40L−/− mice did not elicit CD4+ and CD8+ T cell immunity, even though the DCs exhibited presented ovalbumin on major histocompatibility complex class I and II products and expressed high levels of CD80/86. Likewise, an injection of TNF-α up-regulated CD80/86 on DCs, but CD40 was required for immunity. CD40 was needed for DC interleukin (IL)-12 production, but IL-12p40−/− mice generated normal ovalbumin-specific responses. Therefore, the link between innate and adaptive immunity via splenic DCs and innate NKT cells has several components under distinct controls: antigen presentation in the steady state, increases in costimulatory molecules dependent on inflammatory cytokines, and a distinct CD40/CD40L signal that functions together with antigen presentation (“signal one”) and costimulation (“signal two”) to generate functioning CD4+ T helper cell 1 and CD8+ cytolytic T lymphocytes

A Reversible Defect in Natural Killer T Cell Function Characterizes the Progression of Premalignant to Malignant Multiple Myeloma

We studied the function of antitumor T and natural killer T (NKT) cells from the blood and tumor bed in 23 patients with premalignant gammopathy, nonprogressive myeloma, or progressive multiple myeloma. We show that antitumor killer T cells can be detected in patients with both progressive or nonprogressive myeloma. Vα24+Vβ11+ invariant NKT cells are detectable in the blood and tumor bed of all cohorts. However, freshly isolated NKT cells from both the blood and tumor bed of patients with progressive disease, but not nonprogressive myeloma or premalignant gammopathy, have a marked deficiency of ligand-dependent interferon-γ production. This functional defect can be overcome in vitro using dendritic cells pulsed with the NKT ligand, α-galactosylceramide (α-GalCer). Fresh myeloma cells express CD1d, and can be efficiently killed by autologous NKT cells. We hypothesize that presentation of tumor derived glycolipids by myeloma cells leads to NKT dysfunction in vivo. These data demonstrate that clinical progression in patients with monoclonal gammopathies is associated with an acquired but potentially reversible defect in NKT cell function and support the possibility that these innate lymphocytes play a role in controlling the malignant growth of this incurable B cell tumor in patients

Study on variation of neutral temperature in the polar MLT region using a sodium LIDAR at Tromsø

第2回極域科学シンポジウム/第35回極域宙空圏シンポジウム 11月14日（月） 国立極地研究所 2階大会議

Role of Neuroimaging on Differentiation of Parkinson’s Disease and Its Related Diseases

An accurate diagnosis of Parkinson’s disease (PD) is a prerequisite for therapeutic management. In spite of recent advances in the diagnosis of parkinsonian disorders, PD is misdiagnosed in between 6 and 25% of patients, even in specialized movement disorder centers. Although the gold standard for the diagnosis of PD is a neuropathological assessment, neuroimaging has been playing an important role in the differential diagnosis of PD and is used for clinical diagnostic criteria. In clinical practice, differential diagnoses of PD include atypical parkinsonian syndromes such as dementia with Lewy bodies, multiple system atrophy, progressive supranuclear palsy, corticobasal degeneration, caused by a striatal dopamine deficiency following nigrostrial degeneration. PD may also be mimicked by syndromes not associated with a striatal dopamine deficiency such as essential tremor, drug-induced parkinsonism, and vascular parkinsonism. Moreover, difficulties are associated with the clinical differentiation of patients with parkinsonism from those with Alzheimer’s disease. In this review, we summarize the typical imaging findings of PD and its related diseases described above using morphological imaging modalities (conventional MR imaging and neuromelanin MR imaging) and functional imaging modalities (99mTc-ethyl cysteinate dimer perfusion single photon emission computed tomography, 123I-metaiodobenzylguanidine myocardial scintigraphy, and 123I-FP-CIT dopamine transporter single photon emission computed tomography) that are clinically available in most hospitals. We also attempt to provide a diagnostic approach for the differential diagnosis of PD and its related diseases in clinical practice

Innate NKT lymphocytes confer superior adaptive immunity via tumor-capturing dendritic cells

If irradiated tumor cells could be rendered immunogenic, they would provide a safe, broad, and patient-specific array of antigens for immunotherapies. Prior approaches have emphasized genetic transduction of live tumor cells to express cytokines, costimulators, and surrogate foreign antigens. We asked if immunity could be achieved by delivering irradiated, major histocompatibility complex–negative plasmacytoma cells to maturing mouse dendritic cells (DCs) within lymphoid organs. Tumor cells injected intravenously (i.v.) were captured by splenic DCs, whereas subcutaneous (s.c.) injection led only to weak uptake in lymph node or spleen. The natural killer T (NKT) cells mobilizing glycolipid α-galactosyl ceramide, used to mature splenic DCs, served as an effective adjuvant to induce protective immunity. This adjuvant function was mimicked by a combination of poly IC and agonistic αCD40 antibody. The adjuvant glycolipid had to be coadministered with tumor cells i.v. rather than s.c. Specific resistance was generated both to a plasmacytoma and lymphoma. The resistance afforded by a single vaccination lasted >2 mo and required both CD4+ and CD8+ T cells. Mature tumor capturing DCs stimulated the differentiation of P1A tumor antigen-specific, CD8+ T cells and uniquely transferred tumor resistance to naive mice. Therefore, the access of dying tumor cells to DCs that are maturing to activated NKT cells efficiently induces long-lived adaptive resistance

オウシュウ ヒカンショウ サンラン (EISCAT) レーダー カンソクジョ ノ タハチョウ フォトメータデータ ヲ モチイタ ソウジョウ デンリケン デンドウド ノ スイテイ

本研究では,多波長フォトメータデータ(427.8 nm, 557.7 nm, 630.0 nm)を利用してオーロラ発生時の高緯度電離圏における電気伝導度推定の手法開発を行った.本手法の特徴は層状の電気伝導度を導出することが可能な点である.この層構造を持つ電気伝導度を光学データから導出するためのモデル関数を,高度分解能がある欧州非干渉散乱(EISCAT)UHF レーダーデータから推定した電気伝導度を用いて決定した.本研究により,電離圏を3 層(高度95-110 km, 110-170 km, 170-300 km)に分割しても,従来の方法と同程度の信頼度を持つ電気伝導度を光学データから導出できることが確認された.This study aimed to develop a methodology for estimating ionospheric conductance at auroral latitudes using data from a multi-wavelength photometer (427.8, 557.7, and 630.0 nm). An advantage of the approach is that the ionosphere is divided into layers and conductance is computed for each layer. From optical data, the layer conductance was determined by using height-resolved conductivity derived from the European Incoherent Scatter (EISCAT) Tromso UHF radar. The developed method can provide conductance from optical data with some confidence (at least at the same level as previous methods) even after separating the ionosphere into three layers, 95-110 km, 110-170 km, and 170-300 km