Clonal diversity shapes the tumour microenvironment leading to distinct immunotherapy responses in metastatic urothelial carcinoma
Repeated oncogenic mutations and polyclonal proliferation are evident in cancers. However, little is known about the polyclonal principles governing the systemic cancerous lineage during immunotherapy. Here, we examine a unique autopsy case of metastatic urothelial carcinoma that exhibits different treatment responses to anti-PD-1 therapy at each tumor site. By performing in-depth analyses of different multiregional bulk tumor masses, we reveal that subsets of subclones acquire potential driver mutations under treatment selection pressure. Spatial transcriptomics analysis reveals that subclones resistant to immunotherapy form distinct immunosuppressive environments consistent with their habitats. Furthermore, different cancer hallmarks are identified in each of the subclones that expand under immunotherapy at single-cell level; for example, one subclone is more proliferative, and another is more stem-cell-like. In summary, this study provides an overall picture of the polyclonal competition and changes in the immune microenvironment that are related to resistance to immunotherapy in patients with malignancies.
Authors
- Tomohiro Iwasawa
- Kazuhiro Matsumoto (ORCID: https://orcid.org/0000-0001-9222-0999)
- Takashi Kamatani (ORCID: https://orcid.org/0000-0001-7164-0513)
- Kazuhiro Kakimi (ORCID: https://orcid.org/0000-0003-2631-3040)
- Nobuyuki Tanaka (ORCID: https://orcid.org/0000-0003-0841-9167)
- Kota Umeda
- Mamoru Kato (ORCID: https://orcid.org/0000-0002-8485-8316)
- Tatsuhiko Tsunoda (ORCID: https://orcid.org/0000-0002-5439-7918)
- Jo Nishino (ORCID: https://orcid.org/0000-0001-7057-3048)
- Fuyuki Miya (ORCID: https://orcid.org/0000-0001-6758-2015)
- Yutaka Suzuki (ORCID: https://orcid.org/0000-0003-4852-1879)
- Masayuki Shimoda (ORCID: https://orcid.org/0000-0003-4929-6546)
- Mototsugu Oya
- S Mikami
- Kensuke HARA
Institutions
- Tokyo Institute of Technology (JP)
- Jikei University School of Medicine (JP)
- Chiba University (JP)
- Keio University (JP)
- National Cancer Centre Japan (JP)
- The Cancer Institute Hospital (JP)
- National Hospital Organization (JP)
- RIKEN Center for Integrative Medical Sciences (JP)
- National Hospital Organization Saitama Hospital
- The University of Tokyo (JP)
- Kindai University (JP)
Publication Details
- Journal
- Nature Communications
- Published
- 2025-08-27
- DOI
- https://doi.org/10.1038/s41467-025-63309-1
- Citations
- 2
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 2.09
Funders
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency