Annual Report 2024
Department of Immunogenomic Medicine
Koyama Shohei, Irie Takuma, Sugiyama Eri, Hoshi Yuta, Owari Takuya, Okumura Genki, Fukuoka Megumi, Lin Yi-Tzu, Sai Atsuo, Ishikawa Jun, Watanabe Sho, Manabe Takahiko, Tanabe Kenji, Machiyama Hirotomo, Hoshino Megumi, Yoshimatsu Sayuri
Introduction
More than a decade has passed since the approval of immune checkpoint inhibitors (ICIs), during which their indications have expanded to include a wide range of malignancies, and long-term outcome data have gradually accumulated. However, despite the advent of various combination strategies, including cancer immunotherapy-based multimodal approaches, the achievement rate of long-term survival remains limited. This has highlighted persistent challenges, including the limited efficacy and durability of treatment responses. Furthermore, it has become increasingly evident that host immune mechanisms play a critical role in cancer progression.
The Team and What We Do
Our division is actively engaged in identifying molecular determinants of therapeutic resistance and immune evasion by conducting comprehensive immune and genomic analyses using clinical specimens obtained from patients who have undergone ICI treatment. Functional validation of candidate targets is performed in murine models to evaluate their potential as novel therapeutic targets. As a core component of the Fundamental Innovative Oncology Core (FIOC), our group provides technical support for tumor immunology research, including multicolor flow cytometry, multiplex immunohistochemistry, immune cell functional assays, RNA sequencing, and single-cell transcriptomics using surgical specimens, biopsies, and body fluid samples. In addition, we are developing spatial profiling techniques applicable to bispecific antibodies and antibody-drug conjugates (ADCs). Current research efforts are focused on: (1) elucidating and targeting membrane-bound molecules on cancer cells that modulate the tumor immune microenvironment; (2) dissecting immune suppressive mechanisms mediated by tumor-infiltrating myeloid cells; and (3) devising strategies to activate antitumor immunity in non-inflamed tumors with limited immune cell infiltration. Through these efforts, we aim to overcome current limitations of cancer immunotherapy and advance the development of personalized immune-based treatment strategies.
Research Activities
Since the launch of our laboratory in April 2024, we have provided research support by conducting multiplex immunohistochemical analyses and data interpretation using archived pathological specimens, in response to requests from research laboratories within the National Cancer Center and affiliated universities. In addition, we initiated ancillary immunological studies for a total of 7 clinical trials in collaboration with pharmaceutical companies and clinical research groups, utilizing clinical specimens. As outcomes of these collaborative efforts, we have published the following research articles: Koganemaru S, Koyama S (corresponding author) et al., Cancer Research Communications, 2025; and Tsuge A, Koyama S (corresponding author) et al., Cancer Immunology Research, 2025.
Clinical Trials
In collaboration with multiple pharmaceutical companies and clinical research groups, we have initiated ancillary immunological studies for a total of seven clinical trials using clinical specimens. These efforts aim to identify biomarkers predictive of therapeutic response and to evaluate immune status within the tumor microenvironment (TME) using our original real-time immune monitoring technology.
Education
We actively accept graduate students from affiliated universities and residents from the National Cancer Center, providing intensive research training and supervision with the aim of degree acquisition. In addition, we also host physician-scientists from the National Cancer Center, offering guidance in basic research. After completing their research in our laboratory, some trainees continue their work in Japan, while others pursue further training abroad, and we continue to support their career development.
Future Prospects
To enhance the therapeutic efficacy of cancer immunotherapy, it is essential to overcome immunosuppressive factors within the tumor immune microenvironment and to promote effective immune activation. In particular, elucidating the mechanisms underlying reduced tumor immunogenicity and immune cell exclusion is critical for developing novel therapeutic strategies against non-inflamed tumors, which have historically been difficult to treat. Moving forward, we aim to further advance and quantify immune and genomic analysis technologies to uncover the molecular basis of treatment resistance and immune escape. Through these efforts, we seek to identify and translate novel therapeutic targets that can help overcome the current limitations of cancer immunotherapy.
List of papers published in 2024
Journal
1. Tsuge A, Watanabe S, Kawazoe A, Togashi Y, Itahashi K, Masuda M, Sai A, Takei S, Muraoka H, Ohkubo S, Sugiyama D, Yan Y, Fukuoka S, Doi T, Shitara K, Koyama S, Nishikawa H. The HSP90 Inhibitor Pimitespib Targets Regulatory T Cells in the Tumor Microenvironment. Cancer immunology research, 13:273-285, 2025
2. Koganemaru S, Koyama S, Suto F, Koga M, Inaki K, Kuwahara Y, Arita T, Hirata T, Goto H, Wada N, Kobayashi M, Shibutani T, Okabayashi T, Nakamaru K, Kawazoe A, Togashi Y, Nishikawa H, Shitara K. The Tumor Immune Microenvironment and Therapeutic Efficacy of Trastuzumab Deruxtecan in Gastric Cancer. Cancer research communications, 5:84-93, 2025
3. Kowash RR, Sabnani M, Gray LT, Deng Q, Saleh NUA, Girard L, Naito Y, Masahiro K, Minna JD, Gerber DE, Koyama S, Liu ZL, Baruah H, Akbay EA. Novel and potent MICA/B antibody is therapeutically effective in KRAS LKB1 mutant lung cancer models. Journal for immunotherapy of cancer, 13:e009867, 2025
4. Nishinakamura H, Shinya S, Irie T, Sakihama S, Naito T, Watanabe K, Sugiyama D, Tamiya M, Yoshida T, Hase T, Yoshida T, Karube K, Koyama S, Nishikawa H. Coactivation of innate immune suppressive cells induces acquired resistance against combined TLR agonism and PD-1 blockade. Science translational medicine, 17:eadk3160, 2025
5. Bando H, Kumagai S, Kotani D, Mishima S, Irie T, Itahashi K, Tanaka Y, Habu T, Fukaya S, Kondo M, Tsushima T, Hara H, Kadowaki S, Kato K, Chin K, Yamaguchi K, Kageyama SI, Hojo H, Nakamura M, Tachibana H, Wakabayashi M, Fukui M, Fuse N, Koyama S, Mano H, Nishikawa H, Shitara K, Yoshino T, Kojima T. Atezolizumab following definitive chemoradiotherapy in patients with unresectable locally advanced esophageal squamous cell carcinoma - a multicenter phase 2 trial (EPOC1802). Nature cancer, 6:445-459, 2025
6. Habu T, Kumagai S, Bando H, Fujisawa T, Mishima S, Kotani D, Nakamura M, Hojo H, Sakashita S, Kinoshita T, Yano T, Mitsunaga S, Nishikawa H, Koyama S, Kojima T. Definitive chemoradiotherapy induces T-cell-inflamed tumor microenvironment in unresectable locally advanced esophageal squamous cell carcinoma. Journal of gastroenterology, 59:798-811, 2024
7. Cousin S, Guégan JP, Shitara K, Palmieri LJ, Metges JP, Pernot S, Fukuoka S, Koyama S, Nishikawa H, Bellera CA, Adenis A, Gomez-Roca CA, Cassier PA, Hollebecque A, Cantarel C, Kind M, Soubeyran I, Vanhersecke L, Bessede A, Italiano A. Identification of microenvironment features associated with primary resistance to anti-PD-1/PD-L1 + antiangiogenesis in gastric cancer through spatial transcriptomics and plasma proteomics. Molecular cancer, 23:197, 2024
8. Aokage K, Koyama S, Kumagai S, Nomura K, Shimada Y, Yoh K, Wakabayashi M, Fukutani M, Furuya H, Miyoshi T, Tane K, Samejima J, Taki T, Hayashi T, Matsubayashi J, Ishii G, Nishikawa H, Ikeda N, Tsuboi M. Efficacy, Safety, and Influence on the Tumor Microenvironment of Neoadjuvant Pembrolizumab plus Ramucirumab for PD-L1-Positive NSCLC: A Phase II Trial (EAST ENERGY). Clinical cancer research, 30:5584-5592, 2024