Annual Report 2021

Department of Immune Medicine

Kazunori Aoki, Chie Kudo, Tomomi Nakahara, Kana Ohashi, Ryouichi Sadahiro, Yoko Kobayashi, Hiroko Shindo, Midori Nakamura, Yukihiro Mizoguchi, Atikemu Kelimu, Yasuhito Matsumura, Kosuke Arai, Masae Ohmaru, Hiroki Ozawa, Yukinori Ozaki, Hideyuki Hayashi, Aya Hirata, Hironori Fukuda, Makiko Yamashita, Kenta Narumi, Miki Nonaka, Yamato Ogiwara, Eri Hashimoto, Mengzhu Zhang, Yukimi Egawa

Introduction

 Although the identification of immune checkpoint blockades (ICBs) is changing the approaches to cancer treatment, the resistant cases for ICBs remain a challenging issue 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 molecular basis in an immune-suppressive tumor microenvironment (TME), and drug resistance mechanisms. The specific activities in 2021 were as follows: 1) Exploration of novel targets for the development of immunotherapy based on the immune TME in lung and pancreatic cancers; 2) Elucidation of the molecular mechanisms underlying treatment resistance in various types of cancers; 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

Exploration of novel targets for the development of immunotherapy based on the immune TME in lung and pancreatic cancers

 To clarify the immune landscape present in lung cancer tissues, we analyzed tumor-infiltrating lymphocyte (TIL) profiles in surgical specimens by flow cytometry, and showed that the adenocarcinoma and the squamous cell carcinoma were classified into three distinct immune subtypes. Using RNA-seq and WES data, we identified the subtype-specifically activated signaling pathways and subtype-specific gene abnormalities. Pancreatic cancer is resistant to ICBs due to a highly immunosuppressive TME, possibly created by reactive desmoplastic stroma. We found that myeloid-derived suppressor cells (MDSCs) were most relevant to the poor prognosis among immune cells, and identified a distinct subpopulation of MDSCs that showed a strong immune suppressive activity, in pancreatic cancer tissues. Furthermore, we elucidated a mechanism of interaction between the cancer-associated fibroblasts (CAFs) and MDSCs. This interaction may be a promising target for changing the immune suppressive TME to an anti-tumor state.

Elucidation of molecular mechanisms underlying treatment resistance in various types of cancers

 In collaboration with internal and external researchers and clinicians, by immunologically and biologically analyzing mouse and human samples, we identified new molecular mechanisms underlying treatment resistance in various types of cancers, such as gastrointestinal cancer and osteosarcoma, and determined the clinical relevancy of the basic findings.

Support of immunological analyses in the co-clinical study of clinical trials

 In collaboration with clinical departments in NCC Hospitals, multicenter clinical trial groups including WJOG and pharmaceutical companies, the department has been conducting and supporting the immunological analyses of clinical samples including peripheral blood mononuclear cells, TILs, serum cytokine levels and comprehensive immune gene expression in co-clinical studies of clinical trials. Using these data, the department identified many molecules and unique cell subsets as biomarkers to define the eligibility and potential responses to the treatments of patients with gastric cancer, and designed and developed new treatment regimens for treating gastrointestinal cancer based on the WJOG-TR results.

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. Elimination of HPV DNA from these cancers can prevent cancer growth. We developed an adenovirus vector which induces multiple breaks in HPV DNA using a CRISPR/Cas9-based double-nicking technology. This adenovirus vector caused negligible off-target effects and strongly suppressed the growth of HPV positive cancers.

Education

 The department has accepted seven medical doctors from universities and hospitals to perform the research on basic cancer immunology. Furthermore, three graduate students (doctoral course) linking with Tokyo Medical and Dental University and Keio University and one student 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 enable us to propose novel immunological classifications, 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 TME through the interaction between cancer cells, stromal cells and immune cells, and molecular aspects of drug-resistant mechanisms. These results could lead to the development of useful immune biomarkers, and open a new perspective on immune therapy for cancer.

List of papers published in 2021

Journal

1. Miyazaki T, Chung S, Sakai H, Ohata H, Obata Y, Shiokawa D, Mizoguchi Y, Kubo T, Ichikawa H, Taniguchi H, Aoki K, Soga T, Nakagama H, Okamoto K. Stemness and immune evasion conferred by the TDO2-AHR pathway are associated with liver metastasis of colon cancer. Cancer science, 113:170-181, 2022

2. Zhang M, Kiyono T, Aoki K, Goshima N, Kobayashi S, Hiranuma K, Shiraishi K, Saya H, Nakahara T. Development of an in vitro carcinogenesis model of human papillomavirus-induced cervical adenocarcinoma. Cancer science, 113:904-915, 2022

3. Ozawa H, Imazeki H, Ogiwara Y, Kawakubo H, Fukuda K, Kitagawa Y, Kudo-Saito C. Targeting AURKA in treatment of peritoneal tumor dissemination in gastrointestinal cancer. Translational oncology, 16:101307, 2022

4. Hanaoka S, Saijou S, Matsumura Y. A Novel and Potent Thrombolytic Fusion Protein Consisting of Anti-Insoluble Fibrin Antibody and Mutated Urokinase. Thrombosis and haemostasis, 122:57-66, 2022

5. Hirata A, Sawai E, Henmi M, Shibasaki C, Mizoguchi Y, Narumi K, Aoki K. Imatinib Mesylate Exerted Antitumor Effect by Promoting Infiltration of Effector T Cells in Tumor. Biological & pharmaceutical bulletin, 45:34-41, 2022

6. Kudo-Saito C, Ogiwara Y, Imazeki H, Boku N, Uemura Y, Zhang R, Kawano-Nagatsuma A, Kojima M, Ochiai A. CD11b+DIP2Ab+LAG3b+ cells facilitate immune dysfunction in colorectal cancer. American journal of cancer research, 11:5428-5439, 2021

7. Kudo-Saito C, Ozaki Y, Imazeki H, Hayashi H, Masuda J, Ozawa H, Ogiwara Y. Targeting Oncoimmune Drivers of Cancer Metastasis. Cancers, 13:2021

8. Imazeki H, Ogiwara Y, Kawamura M, Boku N, Kudo-Saito C. CD11b+CTLA4+ myeloid cells are a key driver of tumor evasion in colorectal cancer. Journal for immunotherapy of cancer, 9:2021

9. Matsumura Y. Barriers to antibody therapy in solid tumors, and their solutions. Cancer science, 112:2939-2947, 2021