Annual Report 2017
Department of Immune Medicine
Kazunori Aoki, Chie Kudo, Makiko Yamashita, Yoko Kobayashi, Akihisa Kondo, Yukihiro Mizoguchi, Takahiro Miyamoto, Ryouichi Sadahiro, Aya Hirata, Yuki Yamamoto, Chihiro Shibasaki, Marina Henmi, Yamato Ogiwara, Eri Sawai, Mami Kawamura, Yuria Sawada, Kenta Narumi, Yukio Ozaki, Takayuki Nakayama
Introduction
Research programs in the Department of Immune Medicine consist of development of novel therapeutic strategies for solid cancers based on the analysis of host-immune response against cancer and development of cancer-targeting technologies. The specific activities in 2017 were as follows: 1) Clarification of molecular mechanism of immune-suppressive microenvironment; 2) Development of inhibitory antibody specific for an immune exhaustion-inducible molecule; 3) Support of immunological analysis in the accompanying research of clinical trials; and 4) Development of cancer-targeting vector using the peptide-display adenovirus library.
Research activities
1. Clarification of molecular mechanism of immune suppressive microenvironment
Cancer immunotherapy with immune checkpoint inhibitors has shown a significant effect in a variety of cancers. However, approximately half of patients do not respond to the therapies. The reason behind this ineffectiveness is considered that cancer tissues construct strong immune suppressive tumor microenvironment (TME). In general, cells in the TME can be categorized into three groups: cancer cells, immune cells, and stromal cells. In addition to cancer cells, a third player, stromal cells, also interact with immune cells to influence host-immune reaction. Our department has focused on the interplay between cancer-associated fibroblasts (CAFs) and immune suppressor cells. First, this department established more than 10 CAF lines derived from pancreatic cancer and lung cancer surgical specimens. By using a multiplex protein array and single cell RNA sequencing technologies, the department found that the several molecules produced by CAFs influenced the migration and proliferation/activation of immune suppressive cells such as myeloid-derived suppressor cells and regulatory T cells more strongly than cancer cells did. The findings may lead to the development of novel biomarkers and immune-oncology drugs.
2. Development of inhibitory antibody specific for an immune exhaustion-inducible molecule
Immune exhaustion and dysfunction are frequently caused by cancer, unhealthy aging and life-style, and hyper-reaction after blocking immune checkpoint pathways, and are very hard to be recovered by the present treatments. Therefore, this department has pursued the tumor immunological and biological research for elucidating molecular mechanisms involved there, and has been developing inhibitory antibody drugs targeting several key molecules for treating cancer in collaboration with companies. In parallel, the department has been also conducting a large-scale clinical study using clinical specimens in order to reveal the causal relationships between target molecular expressions and prognosis of patients in collaboration with clinicians and companies.
3. Support of immunological analysis in the accompanying research of clinical trials
In collaboration with each clinical department in the National Cancer Center Hospital (NCCH), our department has participated in the formulation of research plans from the initial stage. Moreover, as the accompanying research of clinical trials, we have supported the immunological analysis of clinical samples including peripheral blood mononuclear cells, tumor-infiltrating lymphocytes and cytokines in the blood to understand the mechanisms of responsiveness and resistance for immune therapies, and explore the novel biomarkers.
4. Development of pancreatic cancer-targeting vector using the peptide-display adenovirus library
Although oncolytic adenovirus is a promising therapeutic strategy for cancer, the recent results of clinical studies show that the cancer-targetablity in a vector is necessary to enhance oncolytic activity and secure safety. This department has previously identified two pancreatic cancer-targeting ligands, SYENFSA (SYE) and PFWSGAV (PFW), by screening our original adenovirus (Ad) library displaying random peptides against pancreatic cancer cells. A survivin promoter-regulated oncolytic Ad displaying the SYE ligand (AdSur-SYE) showed high gene transduction efficiency and oncolytic potency than the non-targeting virus for pancreatic ductal adenocarcinoma (PDAC) as well as for pancreatic neuroendocrine tumors (PNETs). Furthermore, we assessed gene-transduction efficiency of two vectors displaying PFW and SYE using ascites cells of patients with PDAC. Both vectors increased gene-transduction efficiency of epithelial cell adhesion molecule-positive ascites cells. The results indicated that the vectors show promise as a next-generation therapy for PDAC and PNET.
Education
Two chief residents in the NCCH, one graduate student (doctoral course) in Kyorin University, three graduate students (doctoral course: one, master course: two) linking with Tokyo Medical and Dental University, one graduate student (master course) and two students in Tokyo University of Pharmacy and Life Sciences, and one student in Imperial College London studied about cancer immunology and oncolytic virus therapy in our department.
Future prospects
We are investigating the molecular basis of immune-suppressive microenvironment through the interaction between cancer cells, stromal cells and immune cells in TME, and molecular mechanism of immune exhaustion and dysfunction, which may open a new perspective on immunotherapy for cancer. In addition, tumor-targeting oncolytic vectors are also promising as a next-generation of molecular targeting therapy.
List of papers published in January 2017 - March 2018
Journal
1. Yamamoto Y, Nagasato M, Yoshida T, Aoki K. Recent advances in genetic modification of adenovirus vectors for cancer treatment. Cancer Sci, 108:831-837, 2017
2. Nagasato M, Rin Y, Yamamoto Y, Henmi M, Hiraoka N, Chiwaki F, Matsusaki K, Tagawa M, Sasaki H, Aoki K. A Tumor-targeting Adenovirus with High Gene-transduction Efficiency for Primary Pancreatic Cancer and Ascites Cells. Anticancer Res, 37:3599-3605, 2017
3. Shoji H, Tada K, Kitano S, Nishimura T, Shimada Y, Nagashima K, Aoki K, Hiraoka N, Honma Y, Iwasa S, Takashima A, Kato K, Boku N, Honda K, Yamada T, Heike Y, Hamaguchi T. The peripheral immune status of granulocytic myeloid-derived suppressor cells correlates the survival in advanced gastric cancer patients receiving cisplatin-based chemotherapy. Oncotarget, 8:95083-95094, 2017
4. Yamamoto Y, Nagasato M, Rin Y, Henmi M, Ino Y, Yachida S, Ohki R, Hiraoka N, Tagawa M, Aoki K. Strong antitumor efficacy of a pancreatic tumor-targeting oncolytic adenovirus for neuroendocrine tumors. Cancer Med, 6:2385-2397, 2017
5. Kinoshita T, Kudo-Saito C, Muramatsu R, Fujita T, Saito M, Nagumo H, Sakurai T, Noji S, Takahata E, Yaguchi T, Tsukamoto N, Hayashi Y, Kaseda K, Kamiyama I, Ohtsuka T, Tomizawa K, Shimoji M, Mitsudomi T, Asamura H, Kawakami Y. Determination of poor prognostic immune features of tumour microenvironment in non-smoking patients with lung adenocarcinoma. Eur J Cancer, 86:15-27, 2017