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Featured researches published by Yosuke Ohno.


Cancer Science | 2017

IL-6/STAT3 signaling as a promising target to improve the efficacy of cancer immunotherapy.

Hidemitsu Kitamura; Yosuke Ohno; Yujiro Toyoshima; Junya Ohtake; Shigenori Homma; Hideki Kawamura; Norihiko Takahashi; Akinobu Taketomi

Overcoming the immunosuppressive state in tumor microenvironments is a critical issue for improving the efficacy of cancer immunotherapy. Interleukin (IL)‐6, a pleiotropic cytokine, is highly produced in the tumor‐bearing host. Previous studies have indicated that IL‐6 suppresses the antigen presentation ability of dendritic cells (DC) through activation of signal transducer and activator of transcription 3 (STAT3). Thus, we focused on the precise effect of the IL‐6/STAT3 signaling cascade on human DC and the subsequent induction of antitumor T cell immune responses. Tumor‐infiltrating CD11b+CD11c+ cells isolated from colorectal cancer tissues showed strong induction of the IL‐6 gene, downregulated surface expression of human leukocyte antigen (HLA)‐DR, and an attenuated T cell‐stimulating ability compared with those from peripheral blood mononuclear cells, suggesting that the tumor microenvironment suppresses antitumor effector cells. In vitro experiments revealed that IL‐6‐mediated STAT3 activation reduced surface expression of HLA‐DR on CD14+ monocyte‐derived DC. Moreover, we confirmed that cyclooxygenase 2, lysosome protease and arginase activities were involved in the IL‐6‐mediated downregulation of the surface expression levels of HLA class II on human DC. These findings suggest that IL‐6‐mediated STAT3 activation in the tumor microenvironment inhibits functional maturation of DC to activate effector T cells, blocking introduction of antitumor immunity in cancers. Therefore, we propose in this review that blockade of the IL‐6/STAT3 signaling pathway and target molecules in DC may be a promising strategy to improve the efficacy of immunotherapies for cancer patients.


Cancer Immunology, Immunotherapy | 2016

IL-6 down-regulates HLA class II expression and IL-12 production of human dendritic cells to impair activation of antigen-specific CD4(+) T cells.

Yosuke Ohno; Hidemitsu Kitamura; Norihiko Takahashi; Junya Ohtake; Shun Kaneumi; Kentaro Sumida; Shigenori Homma; Hideki Kawamura; Nozomi Minagawa; Susumu Shibasaki; Akinobu Taketomi

Immunosuppression in tumor microenvironments critically affects the success of cancer immunotherapy. Here, we focused on the role of interleukin (IL)-6/signal transducer and activator of transcription (STAT3) signaling cascade in immune regulation by human dendritic cells (DCs). IL-6-conditioned monocyte-derived DCs (MoDCs) impaired the presenting ability of cancer-related antigens. Interferon (IFN)-γ production attenuated by CD4+ T cells co-cultured with IL-6-conditioned MoDCs corresponded with decreased DC IL-12p70 production. Human leukocyte antigen (HLA)-DR and CD86 expression was significantly reduced in CD11b+CD11c+ cells obtained from peripheral blood mononuclear cells (PBMCs) of healthy donors by IL-6 treatment and was STAT3 dependent. Arginase-1 (ARG1), lysosomal protease, cathepsin L (CTSL), and cyclooxygenase-2 (COX2) were involved in the reduction of surface HLA-DR expression. Gene expressions of ARG1, CTSL, COX2, and IL6 were higher in tumor-infiltrating CD11b+CD11c+ cells compared with PBMCs isolated from colorectal cancer patients. Expression of surface HLA-DR and CD86 on CD11b+CD11c+ cells was down-regulated, and T cell-stimulating ability was attenuated compared with PBMCs, suggesting that an immunosuppressive phenotype might be induced by IL-6, ARG1, CTSL, and COX2 in tumor sites of colorectal cancer patients. There was a relationship between HLA-DR expression levels in tumor tissues and the size of CD4+ T and CD8+ T cell compartments. Our findings indicate that IL-6 causes a dysfunction in human DCs that activates cancer antigen-specific Th cells, suggesting that blocking the IL-6/STAT3 signaling pathway might be a promising strategy to improve cancer immunotherapy.


Cancer Science | 2017

Lack of interleukin-6 in the tumor microenvironment augments type-1 immunity and increases the efficacy of cancer immunotherapy

Yosuke Ohno; Yujiro Toyoshima; Hideaki Yurino; Norikazu Monma; Huihui Xiang; Kentaro Sumida; Shun Kaneumi; Satoshi Terada; Shinichi Hashimoto; Kazuho Ikeo; Shigenori Homma; Hideki Kawamura; Norihiko Takahashi; Akinobu Taketomi; Hidemitsu Kitamura

Conquering immunosuppression in tumor microenvironments is crucial for effective cancer immunotherapy. It is well known that interleukin (IL)‐6, a pleiotropic cytokine, is produced in the tumor‐bearing state. In the present study, we investigated the precise effects of IL‐6 on antitumor immunity and the subsequent tumorigenesis in tumor‐bearing hosts. CT26 cells, a murine colon cancer cell line, were intradermally injected into wild‐type and IL‐6‐deficient mice. As a result, we found that tumor growth was decreased significantly in IL‐6‐deficient mice compared with wild‐type mice and the reduction was abrogated by depletion of CD8+ T cells. We further evaluated the immune status of tumor microenvironments and confirmed that mature dendritic cells, helper T cells and cytotoxic T cells were highly accumulated in tumor sites under the IL‐6‐deficient condition. In addition, higher numbers of interferon (IFN)‐γ‐producing T cells were present in the tumor tissues of IL‐6‐deficient mice compared with wild‐type mice. Surface expression levels of programmed death‐ligand 1 (PD‐L1) and MHC class I on CT26 cells were enhanced under the IL‐6‐deficient condition in vivo and by IFN‐γ stimulation in vitro. Finally, we confirmed that in vivo injection of an anti‐PD‐L1 antibody or a Toll‐like receptor 3 ligand, polyinosinic‐polycytidylic acid, effectively inhibited tumorigenesis under the IL‐6‐deficient condition. Based on these findings, we speculate that a lack of IL‐6 produced in tumor‐bearing host augments induction of antitumor effector T cells and inhibits tumorigenesis in vivo, suggesting that IL‐6 signaling may be a promising target for the development of effective cancer immunotherapies.


Scientific Reports | 2015

IL-11 induces differentiation of myeloid-derived suppressor cells through activation of STAT3 signalling pathway

Kentaro Sumida; Yosuke Ohno; Junya Ohtake; Shun Kaneumi; Takuto Kishikawa; Norihiko Takahashi; Akinobu Taketomi; Hidemitsu Kitamura

Myeloid-derived suppressor cells (MDSCs) are immune negative regulators in the tumour microenvironment. Interleukin (IL)-11, a member of IL-6 family cytokines, functions through the unique receptor IL-11 receptor α coupled with the common signal transducer gp130. IL-11-gp130 signalling causes activation of the JAK/STAT3 pathway. IL-11 is highly upregulated in many types of cancers and one of the most important cytokines during tumourigenesis and metastasis. However, the precise effect of IL-11 on differentiation into MDSCs is still unknown. Here, we found that CD11b+CD14+ monocytic MDSCs were generated from peripheral blood mononuclear cells (PBMCs) of healthy donors in the presence of IL-11. IL-11-conditioned PBMCs induced higher expression of immunosuppressive molecules such as arginase-1. A reduction of T-cell proliferation was observed when MDSCs generated in the presence of IL-11 were co-cultured with CD3/CD28-stimulated, autologous T cells of healthy donors. Culture of normal PBMCs with IL-11 led to STAT3 phosphorylation and differentiation into MDSCs via STAT3 activation. We confirmed expressions of both IL-11 and phosphorylated STAT3 in tumour tissues of colorectal cancer patients. These findings suggest that monocytic MDSCs may be induced by IL-11 in the tumour microenvironment. Thus, IL-11-mediated regulation in functional differentiation of MDSCs may serve as a possible target for cancer immunotherapy.


The Journal of Allergy and Clinical Immunology | 2015

Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells.

Junya Ohtake; Shun Kaneumi; Mishie Tanino; Takuto Kishikawa; Satoshi Terada; Kentaro Sumida; Kazutaka Masuko; Yosuke Ohno; Toshiyuki Kita; Sadahiro Iwabuchi; Toshiya Shinohara; Yoshinori Tanino; Tamiko Takemura; Shinya Tanaka; Hiroya Kobayashi; Hidemitsu Kitamura

Title Neuropeptide signaling through neurokinin-1 and neurokinin-2 receptors augments antigen presentation by human dendritic cells Author(s) Ohtake, Junya; Kaneumi, Shun; Tanino, Mishie; Kishikawa, Takuto; Terada, Satoshi; Sumida, Kentaro; Masuko, Kazutaka; Ohno, Yosuke; Kita, Toshiyuki; Iwabuchi, Sadahiro; Shinohara, Toshiya; Tanino, Yoshinori; Takemura, Tamiko; Tanaka, Shinya; Kobayashi, Hiroya; Kitamura, Hidemitsu Citation Journal of Allergy and Clinical Immunology, 136(6): 1690-1694


Asian Journal of Endoscopic Surgery | 2018

Laparoscopic total gastrectomy for advanced gastric cancer in a patient with situs inversus totalis

Kengo Shibata; Hideki Kawamura; Nobuki Ichikawa; Kazuaki Shibuya; Tadashi Yoshida; Yosuke Ohno; Shigenori Homma; Akinobu Taketomi

Situs inversus totalis (SIT) is a rare congenital anomaly. Generally, laparoscopic surgery is difficult to perform in patients with SIT because of both the potential challenges associated with unexpected vascular anomalies and the lack of standardized strategy for handling such cases. This is the first report of laparoscopic total gastrectomy with lymph node dissection for advanced gastric cancer in a patient with SIT. A 79‐year‐old man with SIT was diagnosed with advanced gastric cancer. We performed laparoscopic total gastrectomy with modified D2 lymph node dissection (D2 without splenectomy) and esophagojejunal anastomosis using an overlap method involving retrocolic Roux‐en‐Y reconstruction. The total operating time was 232 min, and blood loss was 110 mL. There were no postoperative complications. In summary, laparoscopic total gastrectomy for gastric cancer can be performed safely, even in a patient with SIT.


Surgical Case Reports | 2017

Usefulness of PET/CT for early detection of internal malignancies in patients with Muir-Torre syndrome : report of two cases

Yui Ishiguro; Shigenori Homma; Tadashi Yoshida; Yosuke Ohno; Nobuki Ichikawa; Hideki Kawamura; Hiroo Hata; Satoru Kase; Susumu Ishida; Hiromi Okada-Kanno; Kanako C. Hatanaka; Akinobu Taketomi

BackgroundMuir–Torre syndrome (MTS) is a rare autosomal dominant genodermatosis caused by mutations in mismatch repair genes. It is characterized by the presence of at least one sebaceous skin tumor associated with internal malignancies. Whether positron emission tomography/computed tomography (PET/CT) is useful for the detection of malignancies in patients with MTS has not been determined. We herein report two cases in which PET/CT was useful for the diagnosis and follow-up of internal malignancies in patients with MTS.Case presentationIn case 1, a 57-year-old woman underwent excision of a sebaceous carcinoma on the left upper eyelid. She underwent follow-up PET/CT once yearly thereafter. Forty-two months after the eyelid surgery, PET/CT showed intense tracer uptake in the right lower abdomen. An ascending colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. In case 2, a 77-year-old man presented for evaluation of three continuous papules with telangiectasia on his right cheek. Examination of a skin biopsy specimen of the cheek papule revealed a sebaceous carcinoma. He underwent PET/CT to detect other malignancies. PET/CT showed intense tracer uptake in the sigmoid colon. A sigmoid colon tumor was identified, and examination of a biopsy specimen showed adenocarcinoma. Both patients underwent resection of their tumors, and both were still free of recurrence of the sebaceous and colon carcinomas at the time of this writing.ConclusionPET/CT is a reliable imaging modality for the detection of internal malignancies and is useful for the diagnosis and follow-up of MTS.


Molecular and Clinical Oncology | 2018

Carcinoma in the residual rectum of a long‑standing Crohn's disease patient following subtotal colectomy: A case report

Kazuaki Shibuya; Shigenori Homma; Tadashi Yoshida; Yosuke Ohno; Nobuki Ichikawa; Hideki Kawamura; Teppei Imamoto; Yoshihiro Matsuno; Akinobu Taketomi

The development of colorectal cancer in long-standing Crohns disease (CD) patients has become a major complication. Therapeutic guidelines for CD-associated cancer (CDAC) have already been established in Western countries; however, specific guidelines are not currently available in Japan. Surveillance of the residual intestine for cancer screening is important for long-standing CD patients. The present case report describes the occurrence of rectal carcinoma in a patient with a 25-year history of CD. A 37-year-old male with a 17-year history of CD underwent semi-emergent subtotal colectomy and ileostomy for bowel obstruction secondary to the transverse colon stenosis, and multiple severe stenosis and inflammation. Postoperatively, the patient resumed pharmacological treatment and underwent follow-up colonoscopies at ~1-2-year intervals. Despite continued pharmacological treatment, inflammation continued in the residual rectum. A total of 8 years following the primary operation, colonoscopy revealed inflammatory polyposis at the remnant rectum, which was diagnosed as adenocarcinoma. The interval between the last colonoscopy was 16 months. The patient then underwent laparoscopic abdominoperineal resection, and remained without recurrence for 12 months following resection. Thus, in long-standing CD patients, annual colonoscopy of the residual intestine may be considered for cancer screening, and specific surveillance guidelines for CDAC should be established.


Surgical Laparoscopy Endoscopy & Percutaneous Techniques | 2017

Mentor Tutoring: An Efficient Method for Teaching Laparoscopic Colorectal Surgical Skills in a General Hospital

Nobuki Ichikawa; Shigenori Homma; Tadashi Yoshida; Yosuke Ohno; Hideki Kawamura; Kazuki Wakizaka; Kazuaki Nakanishi; Keizo Kazui; Hiroaki Iijima; Hiroki Shomura; Tohru Funakoshi; Shiro Nakano; Akinobu Taketomi

Objective: We retrospectively assessed the efficacy of our mentor tutoring system for teaching laparoscopic colorectal surgical skills in a general hospital. Materials and Methods: A series of 55 laparoscopic colectomies performed by 1 trainee were evaluated. Next, the learning curves for high anterior resection performed by the trainee (n=20) were compared with those of a self-trained surgeon (n=19). Results: Cumulative sum analysis and multivariate regression analyses showed that 38 completed cases were needed to reduce the operative time. In high anterior resection, the mean operative times were significantly shorter after the seventh average for the tutored surgeon compared with that for the self-trained surgeon. In cumulative sum charting, the curve reached a plateau by the seventh case for the tutored surgeon, but continued to increase for the self-trained surgeon. Conclusions: Mentor tutoring effectively teaches laparoscopic colorectal surgical skills in a general hospital setting.


Surgical Laparoscopy Endoscopy & Percutaneous Techniques | 2017

The Balance Between Surgical Resident Education and Patient Safety in Laparoscopic Colorectal Surgery: Surgical Resident’s Performance has No Negative Impact

Shigenori Homma; Futoshi Kawamata; Tadashi Yoshida; Yosuke Ohno; Nobuki Ichikawa; Susumu Shibasaki; Hideki Kawamura; Norihiko Takahashi; Akinobu Taketomi

Objective: This study aimed to evaluate the feasibility and effectiveness of a comprehensive theoretical and hands-on training program in performing laparoscopic colonic resections under supervision of an expert surgeon. Materials and Methods: Laparoscopic right colectomy was performed in 78 patients (10 with benign disease, 68 with carcinoma). Demographic, intraoperative, pathologic examination, and short-term outcome data were retrospectively compared between 25 patients operated by surgical residents (R group) and 53 patients operated by senior surgeons (S group). The residents who performed surgeries in the R group had between 1 and 6 years after graduation; no experience with open or laparoscopic colorectal surgery was necessary. The residents completed a training program under supervision of a single expert laparoscopic colorectal surgeon, which included 6 steps, from basic skills to certification. Results: There were no differences in patient age, sex, and body mass index between the R and S groups. Significantly more patients in the R group had early cancer and benign lesions (P<0.05). Thirteen of the 16 residents (81.2 %) had not had prior experience with colonic resection. The time of suturing and knot tying in the dry box did not differ between residents and senior surgeons (68 and 69 s, respectively). All the residents performed laparoscopic right colectomy without intraoperative complications. There were no significant differences in operating time (R group: 173±34 min, S group: 172±52 min), mean estimated blood loss (50±111 vs. 49±100 mL), number of lymph nodes dissected (20.8±12.8 vs. 17.1±9.0), and mean postoperative hospital stay (9.1±3.3 vs. 10.7±4.1 d). On the basis of the year of their residency period, all 3 residents at 6 years after graduation had far greater experience than the other residents and therefore performed the surgery with minor verbal support from the expert. However, residents with 1 or 2 years after graduation had to receive guidance provision by the expert during surgery. Conclusions: When supervised and led by an expert laparoscopic surgeon, surgical residents are capable of performing laparoscopic surgery without negative effects on outcomes.

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