Michio Naoe

TNF-α Drives Human CD14+ Monocytes to Differentiate into CD70+ Dendritic Cells Evoking Th1 and Th17 Responses

Many mechanisms involving TNF-α, Th1 responses, and Th17 responses are implicated in chronic inflammatory autoimmune disease. Recently, the clinical impact of anti-TNF therapy on disease progression has resulted in re-evaluation of the central role of this cytokine and engendered novel concept of TNF-dependent immunity. However, the overall relationship of TNF-α to pathogenesis is unclear. Here, we demonstrate a TNF-dependent differentiation pathway of dendritic cells (DC) evoking Th1 and Th17 responses. CD14+ monocytes cultured in the presence of TNF-α and GM-CSF converted to CD14+ CD1alow adherent cells with little capacity to stimulate T cells. On stimulation by LPS, however, they produced high levels of TNF-α, matrix metalloproteinase (MMP)-9, and IL-23 and differentiated either into mature DC or activated macrophages (Mφ). The mature DC (CD83+ CD70+ HLA-DR high CD14low) expressed high levels of mRNA for IL-6, IL-15, and IL-23, induced naive CD4 T cells to produce IFN-γ and TNF-α, and stimulated resting CD4 T cells to secret IL-17. Intriguingly, TNF-α added to the monocyte culture medium determined the magnitude of LPS-induced maturation and the functions of the derived DC. In contrast, the Mφ (CD14highCD70+CD83−HLA-DR−) produced large amounts of MMP-9 and TNF-α without exogenous TNF stimulation. These results suggest that the TNF priming of monocytes controls Th1 and Th17 responses induced by mature DC, but not inflammation induced by activated Mφ. Therefore, additional stimulation of monocytes with TNF-α may facilitate TNF-dependent adaptive immunity together with GM-CSF-stimulated Mφ-mediated innate immunity.

Detection of circulating urothelial cancer cells in the blood using the CellSearch System

Circulating tumor cells (CTCs) have been shown to aid in the therapeutic management of patients. But, only a few attempts have been made at the detection of urothelial cancer cells in the blood. The purpose of this study was to test the hypothesis that CTCs are detected in patients with urothelial cancers using newly developed CellSearch Assay.

Bacillus Calmette-Guérin-pulsed dendritic cells stimulate natural killer T cells and γδT cells

Background:  Immunotherapy with bacillus Calmette‐Guérin (BCG) for bladder cancer is successful, although the precise mechanism is unclear. Natural killer (NK) cells are a candidate for BCG‐activated killer cells, but the roles of other T lymphocytes, such as NKT cells and γδT cells, are not fully understood. Mycobacterium tuberculosis is a potent activator of both NKT cells and γδT cells. However, it is known that the patients prognosis is good if there are increased numbers of dendritic cells (DCs) in the urine after BCG therapy. Therefore, we investigated whether DCs are matured by BCG and whether BCG‐pulsed DCs stimulate NKT cells and γδT cells.

Zoledronate Stimulates γδ T Cells in Prostate Cancer Patients

Androgen deprivation therapy is the mainstay of treatment for prostate cancer. Given its frequent failure, new therapy that reduces prostate cancer progression would be a breakthrough in treating this disease. Bisphosphonates are well-established agents for treating skeletal-related events (SREs) in prostate cancer patients with bone metastases. Exposure to bisphosphonates may not only reduce the incidence of SREs, but also have anticancer effects by modulating a patients immunity. The purpose of this study was to examine the effect of zoledronate (ZOL) on γδ T cells, serum prostate-specific antigen (PSA) levels, and velocities. The effect of ZOL, with and without IL-2, on γδ T cell activation was examined in vitro. Furthermore, the activated state and the number of γδ T cells and changes in serum PSA levels were examined for patients who received ZOL infusion for the prevention of SREs. We found that ZOL activated γδ T cells, and the number of γδ T cell was increased when IL-2 was administered with ZOL in vitro. Comparisons before and after the first ZOL infusion revealed that γδ T cells in peripheral blood were activated by ZOL. Moreover, after the first ZOL treatment, reduction in serum PSA was observed in 3 of 11 patients, and reduction in PSA velocity was observed in 5 of 10 patients. Our findings indicate that ZOL stimulates γδ T cells in vivo and in vitro. This study provides further insight into the ability of γδ T cells to induce an antitumor immune response.

Correlation between major histocompatibility complex class I molecules and CD8+ T lymphocytes in prostate, and quantification of CD8 and interferon‐γ mRNA in prostate tissue specimens

Objective  To investigate the immunology of host‐tumour interaction, critical for the development of immunotherapy against cancers, by assessing the major histocompatibility complex (MHC) class I expression in both benign and malignant prostate disease, and the relationship between their expression and degree of tumour‐infiltrating lymphocytes.

Papillary cystadenocarcinoma of the prostate

A giant cystic formation was found behind the prostate of a 69‐year‐old man who presented with urinary retention. Ultrasonography, computed tomography scans and magnetic resonance imaging revealed a large cystic intrapelvic mass and biopsy of the cyst wall diagnosed papillary cyst adenocarcinoma. Immunohistochemically, the tumor originated from the prostate.

Practice patterns regarding prostate cancer and benign prostatic hyperplasia in Japanese primary care practitioners.

Objective:  Although primary care practitioners (PCP) take an active role in diagnosis of prostate disorders in Western countries, how PCP take part in management of prostate disease still differs worldwide by country. We investigated practice and referral patterns concerning prostate disease among Japanese PCP and compared these with reported patterns in the West.

腎細胞癌におけるCD83陽性細胞, CD8陽性細胞, CD4陽性細胞の免疫学的検討

OBJECTIVES In order to evaluate the immunological milieu in renal cell carcinoma (RCC), we investigated infiltration by mature dendritic cells (CD83 positive cells), cytotoxic-T cells (CD8 positive cells) and helper-T cells (CD4 positive cells) in RCCs, as well as in surrounding normal tissues and correlations between the cell types. MATERIALS AND METHODS Specimens from 33 surgically resected RCCs were embedded in paraffin and then stained for CD4, CD8, CD83. Each section contained three areas, tumor tissue, tumor margin and normal renal parenchyma. Cells positive for CD4, CD8 and CD83 were counted each area. RESULT Cells positive for CD4, CD8 and CD83 were observed predominantly in the tumor margins, rather than tumor tissue and normal renal parenchyma. The differences were significant in the number of immune positive cells between tumor margin and tumor tissue, and between tumor margin and normal renal parenchyma. A significant correlations was found between CD4 and CD83 positive cells (r = 0.805, p < 0.0001), and also between CD8 and CD83 positive cells (r = 0.505, p < 0.0001). CONCLUSION It has been reported that mature dendritic cells induces cytotoxic-T cell and helper-T cell responses. Infiltrating mature dendritic cells, cytotoxic-T cells and helper-T cells were present only in the tumor margin. This may reflect significant immune reaction around the tumor margin.

Gamma-delta T Cells may Function as Carrier Vehicles in Adenovirus Vector-based Gene Therapy

Developing new treatments that reduce prostate cancer progression is important. Therapeutic efficacy of conventional gene therapy for metastatic prostate cancer is still low. Lower induction rate of naked genes into target cell is due to reduced expression of adenovirus receptor on cancer cell and also due to high seroprevalence of anti-Ad antibodies in adults. Therefore, efficient Ad carrier systems that circumvent these problems should be developed. Gamma-delta T cells have demonstrated high affinity to cancer cells. CD46, which leads to broad tropism in Ad35 vectors, is expressed in hematopoietic cells, including γδ T cells. In this study, we demonstrate the potential of γδ T cells as “vehicles” for transporting Ad5/F35 vectors and genes into cancer cells.

INITIAL EXPERIENCE OF THE ENZALUTAMIDE TREATMENT FOR CASTRATION-RESISTANT PROSTATE CANCER

(Objective) Enzalutamide is an oral androgen-receptor inhibitor that prolongs survival in men with castration-resistant prostate cancer (CRPC). We retrospectively evaluated clinical efficacy and safety of enzalutamide in CRPC. (Patients and methods) We reviewed clinical records of 73 patients who had received enzalutamide for the CRPC at Showa University and affiliated 7 hospitals. Enzalutamide was given at a dose of 160 mg/day, but some patients were treated at lower dose because of there age or poor performance status. Prostrate-specific antigen (PSA) response, prior docetaxel use and the previously administered agents were evaluated retrospectively. (Results) The median patients age was 77 years, the median Gleason score was 9 and the median PSA level at baseline was 26.9 ng/ml. The patients who had prior docetaxel use were 29 (39.7%) and the median of total docetaxel dose was 460 mg/body. The median number of total prior treatments (anti-androgens, Estramustine and steroid) was 3. Twenty seven (61.4%) patients with docetaxel-naïve achieved over 50% reduction of PSA level from baseline, but only 7 (24.1%) in patients previously treated with docetaxel. The most common adverse events included fatigue (24.7%), anorexia (24.7%) and the nausea (16.4%). We found a small proportion of responders to enzalutamide experienced a PSA flare. (Conclusion) Our results of the use of Enzaltamide for CRPC were similar with previous reports. PSA flare was found in some patients with CRPC who responded to enzaltamide. It should be noted that this possible PSA flare phenomenon.