Clonal diversity shapes the tumour microenvironment leading to distinct immunotherapy responses in metastatic urothelial carcinoma

Takashi Kamatani, Kota Umeda, Tomohiro Iwasawa, Fuyuki Miya, Kazuhiro Matsumoto, Shuji Mikami, Kensuke Hara, Masayuki Shimoda, Yutaka Suzuki, Jo Nishino, Mamoru Kato, Kazuhiro Kakimi, Nobuyuki Tanaka (), Mototsugu Oya () and Tatsuhiko Tsunoda ()
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Takashi Kamatani: Institute of Science Tokyo
Kota Umeda: Keio University School of Medicine
Tomohiro Iwasawa: Keio University School of Medicine
Fuyuki Miya: Keio University School of Medicine
Kazuhiro Matsumoto: Keio University School of Medicine
Shuji Mikami: National Hospital Organization Saitama Hospital
Kensuke Hara: Keio University School of Medicine
Masayuki Shimoda: Keio University School of Medicine
Yutaka Suzuki: The University of Tokyo
Jo Nishino: National Cancer Center Japan
Mamoru Kato: National Cancer Center Japan
Kazuhiro Kakimi: Osaka-Sayama
Nobuyuki Tanaka: Keio University School of Medicine
Mototsugu Oya: Keio University School of Medicine
Tatsuhiko Tsunoda: The University of Tokyo

Nature Communications, 2025, vol. 16, issue 1, 1-17

Abstract: Abstract 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.

Date: 2025
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DOI: 10.1038/s41467-025-63309-1

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