Annual Report 2019
Department of Immune Medicine
Kazunori Aoki, Chie Kudo, Makiko Yamashita, Ryouichi Sadahiro, Yoko Kobayashi, Yukihiro Mizoguchi, Midori Nakamura, Atikemu Kelimu, Hiroshi Imazeki, Aya Hirata, Hironori Fukuda, Hiroki Ozawa, Kana Ohashi, Yamato Ogiwara, Eri Hashimoto, Mami Kawamura, Eri Sawai, Masako Tsuzukihashi, Rie Yamazaki, Ayaka Kikuchi, Ayana Sunami, Marcelo Kornexl, Betsan Jones, Takayuki Nakayama, Kenta Narumi, Yukinori Ozaki, Chihiro Kondo, Jun Masuda, Hideyuki Hayashi
Introduction
Cancer immunotherapy with immune checkpoint inhibitors has shown a significant effect in a variety of cancers. However, many patients do not respond to the therapies for a long period. To improve the patient prognosis, the development of novel immune therapy is awaited. Research programs in the Department of Immune Medicine consist of development of novel therapeutic strategies based on the clarification of host-immune response and cell-cell interaction in a tumor microenvironment, and drug response/resistant resistance mechanisms. The specific activities in 2019 were as follows: 1) Clarification of the molecular basis of an immune-suppressive microenvironment in lung cancer and pancreatic cancer tissues; 2) Elucidation of drug-resistant mechanisms and development of new antibody drugs for immune exhaustion; 3) Support of immunological analyses in the co-clinical study of clinical trials.
Research activities
Clarification of molecular basis of immune suppressive microenvironment in lung cancer and pancreatic cancer tissues
To understand the molecular basis of the immune microenvironment in lung cancer for the identification of the novel immune therapy target molecules, we analyzed the tumor infiltrating lymphocytes (TIL) in surgical specimens by flow cytometry, and an unsupervised clustering showed that the adenocarcinoma and the squamous cell carcinoma were classified into three subtypes, respectively, which were closely related to the progression free survival of patients. Then, we extracted the differentially expressed genes in each immunological subtype using RNA-seq data, and identified the subtype-specifically activated signaling pathways and their responsible genes, which might be novel targets for the development of immune therapies. 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 cancer-associated fibroblasts (CAF) isolated from surgical specimens effectively enhanced migratory activity and proliferation/induction of immune suppressive cells such as regulatory T cells and myeloid-derived suppressor cells as compared to pancreatic cancer cells, and identified the responsible genes for CAF-mediated immunological effects by OMICS and immunological analyses. The results suggested that CAF is involved in induction of the immune suppressive microenvironment in pancreatic cancer tissues, and the responsible genes may be promising targets for changing the immune suppressive microenvironment to an anti-tumor state.
Elucidation of drug-resistant mechanisms and development of new antibody drugs for immune exhaustion
We identified the molecular mechanisms underlying resistance to a variety of treatments including chemotherapeutics, molecular targeting inhibitors and immune checkpoint inhibitors. Based on the findings, we have been developing new antibody drugs for successfully eliciting immune responses against cancer in patients in collaboration with companies. To validate the clinical relevancy of the basic findings, we have been conducting five translational research projects in which tumor tissues and peripheral blood obtained from patients are immunologically analyzed, and have lately identified some key molecules responsible for treatment resistance particularly to immune checkpoint inhibitors. Furthermore, we proposed new treatment regimens that were designed on the basis of the basic study to several pharmaceutical companies, and some regimens are now being evaluated toward possible initiation next year.
Support of immunological analyses in the co-clinical study of clinical trials
In collaboration with clinical departments in NCC Hospital, WJOG 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 digital analyzer in co-clinical studies of clinical trials. Using these data, the department revealed key factors of responsiveness and resistance for immune therapies, and explored the novel predictive biomarkers.
Education
The department has accepted 12 medical doctors to perform the research on basic cancer immunology. Furthermore, two graduate students (doctoral course) and three graduate students (master course) linking with Tokyo Medical and Dental University, two students at the University of Exeter, one student at the University of Toronto and two students at Tokyo Biotechnology College studied cancer immunology and immunological analytic technologies in this department. The department has supervised presentations to academic societies and writing graduation theses and scientific manuscripts.
Future prospects
The identification of immunological subtypes in lung cancer may lead to the proposal of novel immunological classification, which is related to treatment choices. Furthermore, we are investigating the molecular basis of an immune-suppressive network in the tumor microenvironment through the interaction between cancer cells, stromal cells and immune cells, and molecular aspects of drug-resistant mechanisms, which may open a new perspective on immune therapy for cancer.
List of papers published in 2019
Journal
1. Takami H, Fukushima S, Aoki K, Satomi K, Narumi K, Hama N, Matsushita Y, Fukuoka K, Yamasaki K, Nakamura T, Mukasa A, Saito N, Suzuki T, Yanagisawa T, Nakamura H, Sugiyama K, Tamura K, Maehara T, Nakada M, Nonaka M, Asai A, Yokogami K, Takeshima H, Iuchi T, Kanemura Y, Kobayashi K, Nagane M, Kurozumi K, Yoshimoto K, Matsuda M, Matsumura A, Hirose Y, Tokuyama T, Kumabe T, Ueki K, Narita Y, Shibui S, Totoki Y, Shibata T, Nakazato Y, Nishikawa R, Matsutani M, Ichimura K. Intratumoural immune cell landscape in germinoma reveals multipotent lineages and exhibits prognostic significance. Neuropathol Appl Neurobiol, 46:111-124, 2020
2. Kudo-Saito C, Miyamoto T, Imazeki H, Shoji H, Aoki K, Boku N. IL33 Is a Key Driver of Treatment Resistance of Cancer. Cancer Res, 80:1981-1990, 2020
3. Yamamoto S, Kato K, Daiko H, Kojima T, Hara H, Abe T, Tsubosa Y, Nagashima K, Aoki K, Mizoguchi Y, Kitano S, Yachida S, Shiba S, Kitagawa Y. Feasibility study of nivolumab as neoadjuvant chemotherapy for locally esophageal carcinoma: FRONTiER (JCOG1804E). Future Oncol, 16:1351-1357, 2020
4. Narumi K, Miyakawa R, Shibasaki C, Henmi M, Mizoguchi Y, Ueda R, Hashimoto H, Hiraoka N, Yoshida T, Aoki K. Local Administration of GITR Agonistic Antibody Induces a Stronger Antitumor Immunity than Systemic Delivery. Sci Rep, 9:5562, 2019