Annual Report 2022
Department of Immune Medicine
Kazunori Aoki, Chie Kudo, Kana Ohashi, Yamato Ogiwara, Ryouichi Sadahiro, Yoko Kobayashi, Hiroko Shindo, Midori Nakamura, Yukihiro Mizoguchi, Yasuhito Matsumura, Susumu Minamisawa, Kosuke Arai, Masae Ohmaru, Yukinori Ozaki, Hiroki Ozawa, Tomomi Nakahara, Miki Nonaka, Eri Hashimoto, Hideyuki Hayashi, Aya Hirata, Hironori Fukuda, Makiko Yamashita
Introduction
Resistance to immune checkpoint blockades (ICBs) remains a challenging issue in recent clinical oncology. However, the mechanism of resistance remains unclear. Research programs in the Department of Immune Medicine consist of developing novel therapeutic strategies based on the elucidation of molecular basis in an immune-suppressive tumor microenvironment (TME), and drug resistance mechanisms. The specific activities in 2022 were as follows: 1) Exploration of molecular basis and intercellular network mechanisms of immune TME in lung and pancreatic cancers; 2) Elucidation of molecular mechanisms underlying treatment resistance in various types of cancers; and 3) Support of immunological analyses in the co-clinical study of clinical trials.
Research Activities
Exploration of molecular basis and intercellular network mechanisms of immune TME in lung and pancreatic cancers
Flow cytometric analysis of tumor-infiltrating lymphocyte (TIL) profile using surgical specimens of lung cancer classified the adenocarcinoma and the squamous cell carcinoma into three distinct immune subtypes (cold, myeloid cell-dominant, T-cell dominant). Further, the subtype-specific gene alterations were identified using RNA-seq and WES data. Clinicopathologic characteristics were examined in respective subtypes, and the myeloid cell-dominant subtype showed worst patient prognosis compared with the other 2 subtypes. In addition, we clarified the immunological characteristics in molecular subtypes of lung cancer adenocarcinoma. Furthermore, the department proceeded the development of subtype-specific immune therapies for lung cancer based on these results. Pancreatic cancer creates a highly immunosuppressive TME, possibly due to reactive desmoplastic stroma. The department found that myeloid-derived suppressor cells (MDSCs) were most relevant to the poor prognosis among immune cells, and identified that a distinct subpopulation of MDSCs existed in pancreatic cancer tissues. Furthermore, the department revealed that cancer-associated fibroblasts (CAFs) interacted with MDSCs via specific chemokines and its receptors. 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
The department elucidated some molecular mechanisms underlying treatment resistance from both basic and clinical aspects in translational research (TR) projects using mouse tumor models and human samples in collaboration with internal and external researchers and clinicians. Based on the results, the department identified several biomarkers to predict possible responders to the immune checkpoint inhibitors, and also designed and developed many treatment regimens that may potentially improve clinical outcomes.
Support of immunological analyses in the co-clinical study of clinical trials
In collaboration with clinical departments in the NCC Hospital, multicenter clinical trial groups and pharmaceutical companies, the department has been conducting and supporting the immunological analyses, including peripheral blood mononuclear cells, TILs, serum cytokine levels and comprehensive immune gene expression in TR studies. 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 cancer, and designed new treatment regimens for treating gastrointestinal cancer. In addition, the department supported the immune profile analysis of human and mouse samples in 3 projects of AMED Practical Research for Innovative Cancer Control as a support team.
Education
The department has accepted six medical doctors from universities and hospitals to perform the research on basic cancer immunology. Furthermore, two graduate students (doctoral course) linking with Tokyo Medical and Dental University studied cancer immunology and immunological analytic technologies in this department
Future Prospects
The classification of distinct immune subtypes and elucidation of molecular basis of TME in lung cancers 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 of various cancers, including pancreatic cancer, gastric cancer and lung cancer through the interaction between cancer cells, stromal cells and immune cells, and molecular aspects of drug-resistant mechanisms. These results from original researches in the department and TRs in collaboration with industry and other academia are useful for promoting the development of novel immune biomarkers and therapeutic strategies for various types of cancer.
List of papers published in 2022
Journal
1. Furuya G, Katoh H, Atsumi S, Hashimoto I, Komura D, Hatanaka R, Senga S, Hayashi S, Akita S, Matsumura H, Miura A, Mita H, Nakakido M, Nagatoishi S, Sugiyama A, Suzuki R, Konishi H, Yamamoto A, Abe H, Hiraoka N, Aoki K, Kato Y, Seto Y, Yoshimura C, Miyadera K, Tsumoto K, Ushiku T, Ishikawa S. Nucleic acid-triggered tumoral immunity propagates pH-selective therapeutic antibodies through tumor-driven epitope spreading. Cancer science, 114:321-338, 2023
2. Yoshida S, Hamada Y, Narita M, Sato D, Tanaka K, Mori T, Tezuka H, Suda Y, Tamura H, Aoki K, Kuzumaki N, Narita M. Elucidation of the mechanisms underlying tumor aggravation by the activation of stress-related neurons in the paraventricular nucleus of the hypothalamus. Molecular brain, 16:18, 2023
3. Fuchigami H, Matsumura Y. Characterization of antibody clones that bind exclusively to insoluble fibrin. Blood coagulation & fibrinolysis, 34:20-27, 2023
4. Wongjampa W, Nakahara T, Tanaka K, Yugawa T, Ekalaksananan T, Kleebkaow P, Goshima N, Kiyono T, Pientong C. An in vitro carcinogenesis model for cervical cancer harboring episomal form of HPV16. PloS one, 18:e0281069, 2023
5. Sadahiro R, Matsuoka LN, Zeng BS, Chen KH, Zeng BY, Wang HY, Chu CS, Stubbs B, Su KP, Tu YK, Wu YC, Lin PY, Chen TY, Chen YW, Suen MW, Hopwood M, Yang WC, Sun CK, Cheng YS, Shiue YL, Hung CM, Matsuoka YJ, Tseng PT. Black cohosh extracts in women with menopausal symptoms: an updated pairwise meta-analysis. Menopause (New York, N.Y.), 2023
6. Osman B, Wang Z, Shiraishi K, Yokoyama M, Matsumura Y. Precipitation of Insoluble Fibrin in the Brains of Alzheimer’s Disease Model Mice. Journal of Blood Disorders, 10:1070, 2023
7. Ogiwara Y, Nakagawa M, Nakatani F, Uemura Y, Zhang R, Kudo-Saito C. Blocking FSTL1 boosts NK immunity in treatment of osteosarcoma. Cancer letters, 537:215690, 2022
8. Takakusagi Y, Sugyo A, Tsuji AB, Sudo H, Yasunaga M, Matsumura Y, Sugawara F, Sakaguchi K, Higashi T. The natural sulfoglycolipid derivative SQAP improves the therapeutic efficacy of tissue factor-targeted radioimmunotherapy in the stroma-rich pancreatic cancer model BxPC-3. Translational oncology, 15:101285, 2022
9. Matsumura Y. 35 years of discussions with Prof. Maeda on the EPR effect and future directions. Journal of controlled release, 348:966-969, 2022
10. Kudo-Saito C, Boku N, Hirano H, Shoji H. Targeting myeloid villains in the treatment with immune checkpoint inhibitors in gastrointestinal cancer. Frontiers in immunology, 13:1009701, 2022
11. Karayama M, Mizoguchi Y, Inoue Y, Hozumi H, Suzuki Y, Furuhashi K, Fujisawa T, Enomoto N, Nakamura Y, Inui N, Suda T, Kitano S, Aoki K, Yamada Y. Association between increased peripheral blood CD86-positive plasmacytoid dendritic cells and immune-related adverse events in patients with non-small cell lung cancer. Global health & medicine, 4:301-308, 2022