Annual Report 2018
Department of Immune Medicine
Kazunori Aoki, Chie Kudo, Makiko Yamashita, Yoko Kobayashi, Yukihiro Mizoguchi, Midori Nakamura, Atikemu Kelimu, Takahiro Miyamoto, Ryouichi Sadahiro, Aya Hirata, Hironori Fukuda, Hiroki Ozawa, Yamato Ogiwara, Eri Sawai, Mami Kawamura, Yuria Sawada, Fion James, Rie Yamazaki, Takayuki Nakayama, Kenta Narumi, Yukinori Ozaki, Chihiro Kondo, Jun Masuda, Hideyuki Hayashi,
Introduction
Research programs in the Department of Immune Medicine consist of development of novel therapeutic strategies based on the clarification of host-immune response and cellcell interaction in a tumor microenvironment, and development of cancer-targeting virotherapy. The specific activities in 2018 were as follows: 1) Clarification of molecular basis of an immunesuppressive microenvironment in lung cancer and pancreatic cancer; 2) Identification of the hyperprogression mechanisms and development of new antibodies for immune exhaustion; 3) Support of immunological analyses in the co-clinical study of clinical trials; and 4) Development of pancreatic cancer-targeting virotherapy.
Research activities
1. Clarification of molecular basis of immune suppressive microenvironment in lung cancer and pancreatic cancer
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. To identify the novel target molecules for development of immune therapy, we took two approaches; 1) to understand the molecular basis of the immune microenvironment in lung cancer, we analyzed the tumor infiltrating lymphocytes (TIL) in surgical specimens, and unsupervised clustering showed that the adenocarcinoma was categorized into three immunological subtypes and the squamous cell carcinoma was categorized into four types. Then, we isolated the differentially expressed genes in each immunological subtype using RNAseq data, and identified the subtype-specifically activated signaling pathways and their responsible genes, which might be novel target molecules and pathways for the development of immune therapies. 2) Pancreatic cancer is resistant to immune checkpoint inhibitors, since it constructs a highly immunosuppressive tumor microenvironment, possibly due to reactive desmoplastic stroma. We found that the cancerassociated fibroblasts (CAF) isolated from surgical specimens effectively enhanced migratory activity and proliferation of immune suppressive cells such as regulatory T cells and myeloid-derived suppressor cells as compared to pancreatic cancer. The analysis of RNA-seq data showed that CAF signature was significantly associated with immune suppressive TIL profiling. These results suggested that CAF involves in induction of the immune suppressive microenvironment in pancreatic cancer.
2. Identification of the hyperprogression mechanisms and development of new antibodies for immune exhaustion
Hyperprogression after treatment with immune checkpoint inhibitors is recently emerging as a serious problem in addition to limited efficacy in the clinical settings. To solve this problem, we identified the underlying molecular mechanisms, and established new immunotherapies for preventing and treating hyperprogression in cancer patients. In addition, we have been generating and establishing antibodies specific for key molecules that we identified as inducers of cancer stemness and immune exhaustion/dysfunction in collaboration with companies.
3. Support of immunological analyses in the coclinical study of clinical trials
In collaboration with clinical departments in the NCC Hospital and pharmaceutical companies, the department has been supporting the immunological analyses of clinical samples including peripheral blood mononuclear cells and tumor-infiltrating lymphocytes by flow cytometry, serum cytokine levels by multiplex assay and comprehensive immune gene expression by the nCounter system in co-clinical studies of clinical trials. Using these data, the department revealed the mechanisms and key factors of responsiveness and resistance to immune therapies, and explored the novel predictive biomarkers. Furthermore, we have been proposing the idea of new therapies based on our basic research to pharmaceutical companies, and some clinical protocols are being prepared in collaboration with clinicians.
4. Development of pancreatic cancer-targeting virotherapy
Although an oncolytic virus is a promising therapeutic strategy for cancer, the recent results of clinical studies show that the cancer-targeting ability in a vector is necessary to enhance oncolytic activity and secure safety. We have previously developed pancreatic cancer-targeting oncolytic adenovirus (AdSur-SYE), which showed a significantly higher oncolytic potency than the non-targeting virus in human PNET and PDAC cell lines, murine models and surgically resected specimens of pancreatic cancer. We identified the cognate receptor for AdSur-SYE, and showed the pancreatic cancer-specific expression pattern of the receptor molecule, which may explain the pancreatic cancer-targeting ability of the AdSurSYE. The results indicated that the vectors are valuable and need to be evaluated in future clinical trials.
Education
Two chief residents in NCC Hospital, one graduate student (doctoral course) at Kyorin University, one graduate student (masters course) linked with Tokyo Medical and Dental University, two graduate students (masters course) at Tokyo University of Pharmacy and Life Sciences, two students at Imperial College London and University of Exeter and one student in Tokyo Biotechnology College studied cancer immunology and immunological analytic technologies in this department.
Future prospects
We are investigating the molecular basis of an immune-suppressive network in a tumor microenvironment through the interaction between cancer cells, stromal cells and immune cells, and the molecular mechanism of immune exhaustion and dysfunction, which may open a new perspective on immune therapy for cancer. In addition, tumor-targeting oncolytic vectors are also promising as a next-generation molecular targeting therapy.
List of papers published in 2018
Journal
1. Henmi M, Shibasaki C, Mizoguchi Y, Hirata A, Sawai E, Narumi K, Aoki K. Pre-immunization of donor lymphocytes with GITR agonistic antibody enhances antitumor immunity in autologous hematopoietic stem cell transplantation. Biochem Biophys Res Commun, 509:96-101, 2019
2. Kudo-Saito C, Ishida A, Shouya Y, Teramoto K, Igarashi T, Kon R, Saito K, Awada C, Ogiwara Y, Toyoura M. Blocking the FSTL1-DIP2A Axis Improves Anti-tumor Immunity. Cell Rep, 24:1790-1801, 2018
3. Lankadasari MB, Aparna JS, Mohammed S, James S, Aoki K, Binu VS, Nair S, Harikumar KB. Targeting S1PR1/STAT3 loop abrogates desmoplasia and chemosensitizes pancreatic cancer to gemcitabine. Theranostics, 8:3824-3840, 2018
4. Hirata A, Hashimoto H, Shibasaki C, Narumi K, Aoki K. Intratumoral IFN-alpha gene delivery reduces tumor-infiltrating regulatory T cells through the downregulation of tumor CCL17 expression. Cancer Gene Ther, 2018