Annual Report 2024
Division of Cancer Immunology
Hiroyoshi Nishikawa, Yuka Maeda, Kosuke Tanaka, Keisuke Watanabe, Eri Sugiyama, Shogo Kumagai, Hitomi Nishinakamura, Sana Hibino, Akihito Nagata, Yuki Okuhiro, Megumi Fukuoka, Sho Watanabe, Lin Yi-Tzu, Carolyne Barakat, Akihito Fukuda, Atsuo Sai, Priya Saju, Yuki Ishige, Megumi Takemura, Yumi Osada, Sayuri Yoshimatsu, Megumi Hoshino, Mizuki Marumo, Kyo Ishin, May Thinzar Hlaing, Abdullah Aimi Naim
Introduction
Cancer immunotherapies such as immune checkpoint inhibitors (ICIs) or chimeric antigen receptor T (CAR-T) cell or T- cell receptor T (TCR-T) cell therapies have become a standard therapy in multiple cancer types. However, only a limited proportion of patients experience durable antitumor efficacy. Cancers often establish a complex immunosuppressive microenvironment that compromises antitumor immune responses, thereby impairing the efficacy of ICIs or adoptive transferred gene-modified T cells. Therefore, there is an urgent need to elucidate the mechanisms of resistance and to identify reliable biomarkers to predict therapeutic efficacy to make immunotherapies much more effective in clinical settings.
The Team and What We Do
We have been collecting clinical samples from cancer patients treated with ICIs or gene-modified cell therapies and intensively investigating the mechanisms of cancer immunoreactions using multi-omics analysis including multicolor flow cytometry, mass cytometry, imaging mass cytometry, single-cell transcriptome analysis, proteomics, and metabolomics (Figure 1). We are also developing first-in-class gene-modified, cell-based immunotherapies using CAR-T cell and TCR-T cell platforms targeting the above mechanisms of resistance.
Figure 1. Integrated multi-omics analyses on patient-derived tumor/immune cell samples.
Research Activities
We have investigated the mechanism(s) by which the efficacy of cancer immunotherapies is impaired using patient-derived samples pre- and post-treatment with ICIs or gene-modified cells. Then, we have elucidated the differentiation process and epigenetic profiles of regulatory T (Treg) cells in the tumor microenvironment (TME). BATF was identified as a key regulator, which leveraged Treg cell differentiation through epigenetically controlling activation-associated gene expression, resulting in the robustness of Treg cells in the TME. We are also developing novel CAR-T cells that overcome multiple immunosuppressive factors; to improve the treatment outcome of adoptive cell therapies in solid tumors. Some are under pre-clinical testing aiming at conducting first-in-human trials. In addition, we have developed a reagent for the combination therapies with anti-PD-1 mAb. This reagent activates the innate immunity via Toll-like receptor signaling. For solid tumors that do not respond to anti-PD-1 mAb therapy, we have analyzed antitumor immune responses by stimulating innate immune responses in tumor-bearing mouse models. The phenotype and proportion of the various immune cells that infiltrate the tumor have been identified, which could lead to the development of a novel combination cancer immunotherapy (Figure 2).
Figure 2. Maximization of antitumor efficacy by triple combination therapy.
Clinical Trials
An investigator-initiated first-in-human trial of our CAR-T cell therapy for relapsed or refractory T cell malignancies is under preparation.
Education
We are hosting graduate students from several universities with partnership agreements, and young residents from the National Cancer Center Hospital for training in translational research. We strongly support their career development, and many alumni are leading the immunology field in a variety of posts in the clinic, academia, or paratheatrical companies.
Future Prospects
We will further investigate the mechanism(s) involved in tumor immune suppression or tumor immune evasion in various cancer types with a broad view into such areas as immunology, metabolomics, and genetics, using new approaches including special and dynamic analysis of the transcriptome or immune cell phenotypes, and transparent mouse tissue models. Our findings will lead to drug discoveries to overcome resistance and to identification of biomarkers in immune therapies. We are planning a first-in-human trial of CAR-T cell therapy for T cell malignancies that has been developed in our laboratory.
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. Wagner M, Nishikawa H, Koyasu S. Reinventing type 2 immunity in cancer. Nature, 637:296-303, 2025
4. Sato T, Sugiyama D, Koseki J, Kojima Y, Hattori S, Sone K, Nishinakamura H, Ishikawa T, Ishikawa Y, Kato T, Kiyoi H, Nishikawa H. Sustained inhibition of CSF1R signaling augments antitumor immunity through inhibiting tumor-associated macrophages. JCI insight, 10:e178146, 2025
5. Moyer A, Tanaka K, Cheng EH. Apoptosis in Cancer Biology and Therapy. Annual review of pathology, 20:303-328, 2025
6. 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
7. 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
8. Kumagai S, Momoi Y, Nishikawa H. Immunogenomic cancer evolution: A framework to understand cancer immunosuppression. Science immunology, 10:eabo5570, 2025
9. Momoi Y, Kumagai S, Nishikawa H. Immunogenomic precision medicine: a personalized approach based on immunogenomic cancer evolution. International immunology, dxaf020, 2025
10. Jinushi K, Saito T, Kurose K, Suzuki S, Kojima T, Takahara T, Makino T, Ogawa T, Nishikawa H, Kakimi K, Iida S, Nakajima J, Doki Y, Oka M, Ueda R, Wada H. Phase I study on neoadjuvant combination immunotherapy with mogamulizumab and nivolumab for solid tumors. Journal for immunotherapy of cancer, 13:e010634, 2025
11. Terasaki F, Sugiura T, Okamura Y, Ashida R, Ohgi K, Yamada M, Ohtsuka S, Uesaka K. Benefit of lymph node dissection for perihilar and distal cholangiocarcinoma according to lymph node stations. Journal of hepato-biliary-pancreatic sciences, 31:251-261, 2024
12. Nishikawa H. Establishment of immune suppression by cancer cells in the tumor microenvironment. Proceedings of the Japan Academy. Series B, Physical and biological sciences, 100:114-122, 2024
13. Kumagai S, Itahashi K, Nishikawa H. Regulatory T cell-mediated immunosuppression orchestrated by cancer: towards an immuno-genomic paradigm for precision medicine. Nature reviews. Clinical oncology, 21:337-353, 2024
14. Fukuda A, Okuma Y. From Rarity to Reality: Osimertinib's Promising Horizon in Treating Uncommon EGFR Mutations in Non-Small Cell Lung Cancer. Clinical cancer research, 30:3128-3136, 2024
15. Yamamoto G, Tanaka K, Kamata R, Saito H, Yamamori-Morita T, Nakao T, Liu J, Mori S, Yagishita S, Hamada A, Shinno Y, Yoshida T, Horinouchi H, Ohe Y, Watanabe SI, Yatabe Y, Kitai H, Konno S, Kobayashi SS, Ohashi A. WEE1 confers resistance to KRAS(G12C) inhibitors in non-small cell lung cancer. Cancer letters, 611:217414, 2024