Annual Report 2024
Department of Immune Medicine
Kazunori Aoki, Chie Kudo, Yukiko Aikawa, Kosuke Arai, Yamato Ogiwara, Ryouichi Sadahiro, Yoko Kobayashi, Midori Nakamura, Yasuko Henmi, Yasuhito Matsumura, Yukinori Ozaki, Tomomi Nakahara, Eri Hashimoto, Hideyuki Hayashi, Hironori Fukuda, Makiko Yamashita, Yoshimi Ohya, Yuri Sakurai, Chihiro Yoshizawa
Introduction
The development of novel therapies for immune checkpoint inhibitors (ICIs) represents a major challenge in clinical oncology. Research programs in the Department of Immune Medicine consist of developing novel therapeutic strategies based on the elucidation of the molecular basis in an immune-suppressive tumor microenvironment (TME), immune network system, and drug resistance mechanisms. The specific activities in 2024 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
Multiple anaplastic lymphoma kinase (ALK) inhibitors are effective for ALK fusion gene-positive lung cancer, but drug resistance eventually develops. ALK-positive lung cancer exhibits resistance to ICIs. The cause of this resistance is thought to be the formation of a highly robust immunosuppressive TME in ALK-positive lung cancer, though the detailed mechanism remains unclear. Through analysis of tumor-infiltrating lymphocyte (TIL) profiles, the department found that the immune TME of lung cancer tissue can be classified into three subtypes: one with low immune cell infiltration, one with a high proportion of myeloid cells, and one with a high proportion of T cells. ALK-positive lung adenocarcinoma belongs to the myeloid subtype and further forms a distinct subclass within it. Furthermore, the mechanisms establishing the myeloid subtype's immune TME are: 1) ALK-positive lung cancer cells inactivate macrophages, thereby suppressing the production of chemokines that recruit T cells from macrophages, leading to a reduction in T cells within the tumor, 2) ALK-positive lung cancer cells produce cytokines that recruit, induce, or activate myeloid-derived suppressor cells (MDSCs), increasing MDSC numbers and establishing a robust immunosuppressive TME. Elucidation of the immune characteristics may lead to the development of personalized immune therapy for ALK-positive lung cancer.
Elucidation of molecular mechanisms underlying treatment resistance in various types of cancers
In translational research (TR) projects with clinicians and pharmaceutical companies, the basic research using mouse tumor models and clinical samples has led not only to the elucidation of several new molecular mechanisms underlying cancer intractability, but also to the identification of several biomarkers to more accurately predict possible responders and nonresponders to anti-PD1/PDL1 mAbs. This research has also contributed to the discovery of target molecules that have the potential to improve clinical outcomes in various types of cancers, such as gastrointestinal cancer, tongue cancer, and breast cancer.
Support of immunological analyses in the co-clinical study of clinical trials
The department has collaborated with clinicians within and outside the NCC, the Multicenter Clinical Trials Group, and pharmaceutical companies to conduct and support immunological analyses—including peripheral blood mononuclear cell and TIL profiling, serum cytokine analysis, and comprehensive immune gene expression profiling—as part of 15 collaborative research projects. Furthermore, utilizing these data, the department identified numerous molecules and specific cell subsets as biomarkers to define treatment eligibility and potential response in cancer patients. Five consultations were conducted with major pharmaceutical companies and others regarding TR involving clinical trials. In addition, the department supported the immune profile analysis of clinical samples in one project of AMED Practical Research for Innovative Cancer Control as a support team.
Education
The department has accepted three medical doctors from universities and hospitals to perform research on basic cancer immunology.
Future Prospects
Elucidating the immunological characteristics of the lung cancer immune TME holds potential for developing novel personalized immunotherapies. Furthermore, the department has been investigating the immunosuppressive 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 2024
Journal
1. Ishihara H, Fukuda H, Mizoguchi Y, Yamashita M, Aoki K, Ishiyama R, Ikeda T, Nemoto Y, Shimmura H, Hashimoto Y, Yoshida K, Hirai T, Iizuka J, Tokita D, Kondo T, Nagashima Y, Takagi T. Sex differences in immunotherapy outcomes and tumor-infiltrating immune cell profiles in patients with advanced renal cell carcinoma. Cancer immunology, immunotherapy : CII, 74:51, 2025
2. Hirano H, Takahashi N, Amanuma Y, Suzuki N, Takahari D, Kawakami T, Kudo-Saito C, Nagashima K, Boku N, Kato K, Shoji H. Phase II trial of nab-paclitaxel plus ramucirumab in combination with nivolumab for unresectable advanced or recurrent gastric cancer after progression on first-line treatment including fluoropyrimidine, platinum, and anti-PD-1/PD-L1 antibody (PADDLE). BMC cancer, 25:201, 2025
3. Kudo-Saito C, Imazeki H, Ozawa H, Kawakubo H, Hirano H, Boku N, Kato K, Shoji H. Targeting SNCA in the treatment of malignant ascites in gastrointestinal cancer. Translational oncology, 48:102075, 2024
4. Kudo-Saito C, Matsumura S, Mori T, Honma Y, Yoshimoto S. Prognostic significance of the FSTL1-DIP2A axis in early-stage tongue cancer. American journal of cancer research, 14:3816-3825, 2024
5. Shoji H, Kudo-Saito C, Nagashima K, Imazeki H, Tsugaru K, Takahashi N, Kawakami T, Amanuma Y, Wakatsuki T, Okano N, Narita Y, Yamamoto Y, Kizawa R, Muro K, Aoki K, Boku N. Myeloid subsets impede the efficacy of anti-PD1 therapy in patients with advanced gastric cancer (WJOG10417GTR study). Journal for immunotherapy of cancer, 12:e010174, 2024
Book
1. Kudo-Saito C, Ozaki Y. Targeting myeloid determinants of breast cancer. In: Rezaei N (ed), Breast Cancer Genetics, Immunology, and Immunotherapy: An Interdisciplinary Approach., Switzerland, Springer Cham, pp 255-285, 2024