Annual Report 2023
Department of Immune Medicine
Kazunori Aoki, Chie Kudo, Yamato Ogiwara, Ryouichi Sadahiro, Yoko Kobayashi, Midori Nakamura,
Yukihiro Mizoguchi, Yasuhito Matsumura, Susumu Minamisawa, Kosuke Arai, Kana Ohashi, Yukinori Ozaki,
Tomomi Nakahara, Miki Nonaka, Eri Hashimoto, Hideyuki Hayashi, Hironori Fukuda, Makiko Yamashita,
Shigehisa Kitano, Yoshimi Ohya
Introduction
Resistance to immune checkpoint blockades (ICBs) remains challenging 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 2023 were as follows: 1) Exploration of the molecular basis and intercellular network mechanisms of the immune TME in lung cancer; 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 the molecular basis and intercellular network mechanisms of the immune TME in lung cancer
The department investigated the immune landscape of non-small lung cancer tissues in molecular subtypes using a multi-omics dataset, including tumor-infiltrating lymphocytes (TILs) profile. Transcriptome analysis shows that adenocarcinoma can be divided into three molecular subtypes: terminal respiratory unit (TRU), proximal proliferative (PP), and proximal inflammatory (PI). In the PI subtype, the number of TILs increased, and the immune response in the TME was activated, as indicated by high levels of tertiary lymphoid structures and high cytotoxic marker levels. Patient prognosis was worse in the PP subtype than in other adenocarcinoma subtypes. GLUT1 expression levels were upregulated, and lactate accumulated in the TME of the PP subtype. This may lead to the formation of an immunosuppressive TME, including the inactivation of antigen-presenting cells. The TRU subtype had low biological malignancy and “cold” tumor-immune phenotypes. ICBs may be an effective treatment for the PI subtype. Glycolysis is a potential target for converting immunosuppressive TME into anti-tumorigenic TME in the PP subtype. The department showed that elucidation of the immune characteristics of molecular subtypes may lead to the development of personalized immune therapy for lung cancer.
Elucidation of molecular mechanisms underlying treatment resistance in various types of cancers
In translational research (TR) projects using mouse tumor models and human samples in collaboration with internal and external researchers and clinicians, the department has led to the elucidation of several new molecular mechanisms underlying resistance to various treatments, including ICBs such as anti-PD1/PD-L1 mAbs and molecularly targeted drugs such as CDK4/6 inhibitors. In addition, the department identified several biomarkers to more accurately predict possible responders to anti-PD1/PD-L1 therapy, and new druggable target molecules that have the potential to improve clinical outcomes, particularly in the treatment of gastrointestinal and breast cancer.
Support of immunological analyses in the co-clinical study of clinical trials
Collaborating with clinical departments in the NCC Hospitals, multicenter clinical trial groups, and pharmaceutical companies, the department has conducted and supported 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. These department's efforts led to seven consultations with major pharmaceutical companies and other organizations regarding TR accompanying clinical trials. In addition, the department supported the immune profile analysis of clinical and animal samples in three 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, one graduate student (doctoral course) linked with Tokyo Medical and Dental University studied cancer immunology and immunological analytic technologies in this department.
Future Prospects
The elucidation of the immunological characteristics in the molecular and immune subtypes of lung cancers may lead to the development of personalized immune therapies. Furthermore, the department has been investigating the immune-suppressive network mechanisms in TME of various cancers, including pancreatic, gastric, 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 research 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 2023
Journal
1. Ohashi K, Nishito Y, Fukuda H, Sadahiro R, Yoshida Y, Watanabe SI, Motoi N, Sonobe Y, Mizuno H, Tsunoda H, Tatsumi K, Suzuki T, Ochiai A, Aoki K. Neutrophil-to-lymphocyte ratio is a prognostic factor reflecting immune condition of tumor microenvironment in squamous cell lung cancer. Scientific reports, 14:429, 2024
2. Fukuda H, Arai K, Mizuno H, Nishito Y, Motoi N, Arai Y, Hiraoka N, Shibata T, Sonobe Y, Kayukawa Y, Hashimoto E, Takahashi M, Fujii E, Maruyama T, Kuwabara K, Nishizawa T, Mizoguchi Y, Yoshida Y, Watanabe SI, Yamashita M, Kitano S, Sakamoto H, Nagata Y, Mitsumori R, Ozaki K, Niida S, Kanai Y, Hirayama A, Soga T, Tsukada K, Yabuki N, Shimada M, Kitazawa T, Natori O, Sawada N, Kato A, Yoshida T, Yasuda K, Ochiai A, Tsunoda H, Aoki K. Molecular subtypes of lung adenocarcinoma present distinct immune tumor microenvironments. Cancer science, 115:1763-1777, 2024
3. Sakashita M, Motoi N, Yamamoto G, Gambe E, Suzuki M, Yoshida Y, Watanabe SI, Takazawa Y, Aoki K, Ochiai A, Sakashita S. An algorithm-based technique for counting mitochondria in cells using immunohistochemical staining of formalin-fixed and paraffin-embedded sections. Journal of cancer research and clinical oncology, 150:172, 2024
4. Oshima K, Shoji H, Boku N, Hirano H, Okita N, Takashima A, Kato K, Kudo-Saito C. CRP and soluble CTLA4 are determinants of anti-PD1 resistance in gastrointestinal cancer. American journal of cancer research, 14:1174-1189, 2024
5. Aoki K, Nishito Y, Motoi N, Arai Y, Hiraoka N, Shibata T, Sonobe Y, Kayukawa Y, Hashimoto E, Takahashi M, Fujii E, Nishizawa T, Fukuda H, Ohashi K, Arai K, Mizoguchi Y, Yoshida Y, Watanabe SI, Yamashita M, Kitano S, Sakamoto H, Nagata Y, Mitsumori R, Ozaki K, Niida S, Kanai Y, Hirayama A, Soga T, Maruyama T, Tsukada K, Yabuki N, Shimada M, Kitazawa T, Natori O, Sawada N, Kato A, Yoshida T, Yasuda K, Mizuno H, Tsunoda H, Ochiai A. Tumor-infiltrating Leukocyte Profiling Defines Three Immune Subtypes of NSCLC with Distinct Signaling Pathways and Genetic Alterations. Cancer research communications, 3:1026-1040, 2023
6. Sri-Iesaranusorn P, Sadahiro R, Murakami S, Wada S, Shimizu K, Yoshida T, Aoki K, Uezono Y, Matsuoka H, Ikeda K, Yoshimoto J. Data-driven categorization of postoperative delirium symptoms using unsupervised machine learning. Frontiers in psychiatry, 14:1205605, 2023
7. Mitsunaga S, Ikeda M, Imaoka H, Sasaki M, Watanabe K, Sato A, Aoki K, Ochiai A, Makikawa M, Nishidate M, Yamaguchi K, Terao K, Sawada N, Fujitomo T, Fujii E, Kato A, Tsunoda H. Fibroblast inhibition by tocilizumab enabled gemcitabine/nab-paclitaxel rechallenge for pancreatic cancer. Cancer science, 114:4006-4019, 2023
8. Nukpook T, Kiyono T, Ekalaksananan T, Kasemsiri P, Teeramatwanich W, Vatanasapt P, Chaiwiriyakul S, Nakahara T, Pientong C. An in vitro model and the underlying pathways of sinonasal inverted papilloma development. Scientific reports, 13:18456, 2023
9. Ozaki Y, Kinowaki K, Kawabata H, Kudo-Saito C. IL25(+) macrophages are a key determinant of treatment resistance of IL17RB(+) breast cancer. American journal of cancer research, 13:4931-4943, 2023
Book
1. Kudo-Saito C, Kinoshita T. Targeting immune determinants of creating tumor heterogeneity in lung cancer. In: Rezaei N (ed), Cancer Research: An Interdisciplinary Approach, Springer, Switzerland, 2023