Annual Report 2020
Department of Immune Medicine
Kazunori Aoki, Chie Kudo, Tomomi Nakahara, Ryouichi Sadahiro, Kana Ohashi, Yasuhito Matsumura, Yoko Kobayashi, Yukihiro Mizoguchi, Midori Nakamura, Atikemu Kelimu, Hiroko Shindo, Hironori Fukuda, Kosuke Arai, Kenta Narumi, Makiko Yamashita, Aya Hirata, Hiroki Ozawa, Yukinori Ozaki, Jun Masuda, Hideyuki Hayashi, Masae Ohmaru, Yukiko Shimoda, Yamato Ogiwara, Eri Hashimoto, Mengzhu Zhang, Masako Tsuzukihashi, Ayaka Kikuchi, Yukimi Egawa, Riria Koyama
Introduction
Although the identification of immune checkpoint blockade (ICB) is changing the approaches to cancer treatment, the resistant cases for ICBs remain to be a challenge among cancer patients. Research programs in the Department of Immune Medicine consist of developing novel therapeutic strategies based on the elucidation of host-immune response and cell-cell interaction in a tumor microenvironment, and drug response/resistance mechanisms. The specific activities in 2020 were as follows: 1) Clarification of molecular basis of immune-suppressive microenvironment in lung and pancreatic cancers; 2) Elucidation of drug-resistant mechanisms and development of new antibody drugs; 3) Support of immunological analyses in the co-clinical study of clinical trials, and 4) Development of a therapeutic vector for HPV-associated cancers by using CRISPR genome editing technology.
Research activities
Clarification of molecular basis of immune suppressive microenvironment in lung and pancreatic cancers
The responsiveness of immune therapy is mainly determined by the quantity, composition and activation status of tumor-infiltrating lymphocytes (TILs). To clarify the immune landscape present in lung cancer tissues, we analyzed TIL profile in surgical specimens by flow cytometry, and showed that the adenocarcinoma and the squamous cell carcinoma were classified into three distinct immune subtypes. Then, using RNA-seq data, we identified the subtype-specifically activated signaling pathways and their responsible genes, which may be useful for developing personalized immune therapies. Pancreatic cancer is resistant to ICBs due to a highly immunosuppressive tumor microenvironment, possibly created by reactive desmoplastic stroma. We found that the cancer-associated fibroblasts (CAF) effectively enhanced migratory activity and proliferation/induction of immune suppressive cells including myeloid-derived suppressor cells as compared to pancreatic cancer cells, and identified the responsible genes for CAF-mediated immunological effects, which 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
We identified the molecular mechanisms underlying resistance to a variety of treatments with agents, including chemotherapeutics, molecular targeting inhibitors and ICBs. Based on the basic and clinical findings, we have been developing antibody drugs targeting the identified mechanisms and genomic and phospho-proteomics panels for diagnosis of immune status to define the eligibility and potential responses of cancer patients to the treatments in clinical settings in collaboration with companies and external institutions. Furthermore, we have been proposing new treatment regimens and exploration plans of the therapeutic mechanisms using the clinical specimens as new translational research studies to several global pharmaceutical companies, two studies have been accepted as new projects to start next term.
Support of immunological analyses in the co-clinical study of clinical trials
In collaboration with clinical departments in NCC Hospitals, external institutions and pharmaceutical companies, the department has been supporting the immunological analyses of clinical samples including peripheral blood mononuclear cells, tumor-infiltrating lymphocytes, serum cytokine levels and comprehensive immune gene expression 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.
Development of a therapeutic vector for HPV-associated cancers by using CRISPR genome editing technology
High-risk HPV infection is responsible for several cancers including cervical and oropharyngeal cancers. Removal of HPV DNA from the cancer cells can prevent the growth and spread of cancers. We developed an adenovirus vector that is designed to induce multiple breaks in HPV DNA using a CRISPR/Cas9-based double-nicking technology, and the vector was shown to markedly reduce cell proliferation, expression of the viral oncoproteins and copy numbers of HPV DNA in HPV-positive cervical cancer cells.
Education
The department has accepted 10 medical doctors from universities and hospitals to perform the research on basic cancer immunology. Furthermore, two graduate students (doctoral course) and one graduate student (master course) linking with Tokyo Medical and Dental University, one student at the University of Exeter, England, and two students at Tokyo Biotechnology College studied cancer immunology and immunological analytic technologies in this department.
Future Prospects
The identification of immune subtypes in lung and pancreatic cancers may be able to propose of novel immunological classification, which may lead to the development of personalized immune therapies. Furthermore, the department has been 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 2020
Journal
1. Arakawa A, Ichikawa H, Kubo T, Motoi N, Kumamoto T, Nakajima M, Yonemori K, Noguchi E, Sunami K, Shiraishi K, Kakishima H, Yoshida H, Hishiki T, Kawakubo N, Kuroda T, Kiyokawa T, Yamada K, Yanaihara N, Takahashi K, Okamoto A, Hirabayashi S, Hasegawa D, Manabe A, Ono K, Matsuoka M, Arai Y, Togashi Y, Shibata T, Nishikawa H, Aoki K, Yamamoto N, Kohno T, Ogawa C. Vaginal Transmission of Cancer from Mothers with Cervical Cancer to Infants. N Engl J Med, 384:42-50, 2021
2. Kudo-Saito C, Ozaki Y, Imazeki H, Hayashi H, Masuda J, Ozawa H, Ogiwara Y. Targeting Oncoimmune Drivers of Cancer Metastasis. Cancers (Basel), 13:2021
3. Shiraishi T, Ikeda K, Tsukada Y, Nishizawa Y, Sasaki T, Ito M, Kojima M, Ishii G, Tsumura R, Saijou S, Koga Y, Yasunaga M, Matsumura Y. High expression of TMEM180, a novel tumour marker, is associated with poor survival in stage III colorectal cancer. BMC Cancer, 21:302, 2021
4. Kudo-Saito C. A possible paradigm shift from targeting immune checkpoint pathways toward targeting oncoimmune drivers in cancer immunotherapy. J Jpn Soc Oral Tumors, 32:144-152, 2020