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Peer-reviewedCC BY 4.0Cancer Immunology, Immunotherapy : CII

Impact of neoadjuvant chemotherapy on the association between key genetic alterations and tumor microenvironment in upper tract urothelial carcinoma

  • Daiki Ikarashi1,2,3
  • Kenta Takahashi1
  • Shigehisa Kitano2,3
  • Daichi Tamura1
  • Masakazu Abe1
  • Ayato Ito1
  • Ei Shiomi1
  • Shigekatsu Maekawa1
  • Renpei Kato1
  • Mitsugu Kanehira1
  • Naoki Yanagawa4
  • Wataru Obara1
4 affiliations
  1. 1Department of Urology, Iwate Medical University School of Medicine, Iwate, 028-3695 Japan
  2. 2Division of Cancer Immunotherapy Development, Department of Advanced Medical Development, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 135-8550 Japan
  3. 3Division of Clinical Chemotherapy, Cancer Chemotherapy Center, Japanese Foundation for Cancer Research, Tokyo, 135-8550 Japan
  4. 4Department of Pathology, Iwate Medical University School of Medicine, Iwate, 028-3695 Japan
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Abstract

Background and Objective: Adjuvant nivolumab has demonstrated clinical benefit in urothelial carcinoma; however, emerging evidence suggests that its efficacy may differ between bladder cancer and upper tract urothelial carcinoma (UTUC), potentially reflecting differences in genomic profiles and the tumor microenvironment (TME). This study aimed to evaluate the association between key oncogenic mutations and the TME characteristics in UTUC, with a particular focus on the impact of neoadjuvant chemotherapy (NAC).

Methods: We analyzed tumor specimens from 32 patients who underwent nephroureterectomy for UTUC. Patients were categorized into NAC and non-NAC groups. Oncogenic mutations (TP53, FGFR3, and RAS) were assessed in all patients, and immune cell densities (CD3+, CD4+, CD8+, Foxp3+, and CD204+) in intratumoral and peritumoral regions were quantified using multiplex fluorescent immunohistochemistry.

Results: TP53, FGFR3, and RAS mutations were identified in 29%, 31%, and 34% of patients, respectively. NAC was administered to 22% of patients. The NAC group demonstrated significantly higher densities of intratumoral CD4+ T cells (p = 0.0201) and a trend toward increased CD8+ T cells (p = 0.0614). Among patients with TP53 mutations, NAC was associated with significantly higher intratumoral CD4+ T cell density (p = 0.0369) compared without NAC. In contrast, FGFR3-mutant tumors exhibited consistently low immune cell infiltration, irrespective of NAC status.

Conclusions: TP53-mutant tumors from patients who received NAC were associated with higher intratumoral CD4⁺ T cell density, whereas FGFR3-mutant tumors exhibited persistently low immune-cell infiltration irrespective of NAC exposure. These findings highlighted distinct mutation-associated TME features in UTUC.

Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04500-1.

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Cite

BibTeXRIS
BibTeX
@article{ikarashi2026impact,
  title = {{Impact of neoadjuvant chemotherapy on the association between key genetic alterations and tumor microenvironment in upper tract urothelial carcinoma}},
  author = {Daiki Ikarashi and Kenta Takahashi and Shigehisa Kitano and Daichi Tamura and Masakazu Abe and Ayato Ito and Ei Shiomi and Shigekatsu Maekawa and Renpei Kato and Mitsugu Kanehira and Naoki Yanagawa and Wataru Obara},
  journal = {Cancer Immunology, Immunotherapy : CII},
  year = {2026},
  month = jul,
  doi = {10.1007/s00262-026-04500-1},
  url = {https://doi.org/10.1007/s00262-026-04500-1},
  note = {CC BY 4.0},
}
RIS
TY  - JOUR
TI  - Impact of neoadjuvant chemotherapy on the association between key genetic alterations and tumor microenvironment in upper tract urothelial carcinoma
AU  - Daiki Ikarashi
AU  - Kenta Takahashi
AU  - Shigehisa Kitano
AU  - Daichi Tamura
AU  - Masakazu Abe
AU  - Ayato Ito
AU  - Ei Shiomi
AU  - Shigekatsu Maekawa
AU  - Renpei Kato
AU  - Mitsugu Kanehira
AU  - Naoki Yanagawa
AU  - Wataru Obara
PY  - 2026
DA  - 2026/07/27
JO  - Cancer Immunology, Immunotherapy : CII
DO  - 10.1007/s00262-026-04500-1
UR  - https://doi.org/10.1007/s00262-026-04500-1
AB  - Background and Objective: Adjuvant nivolumab has demonstrated clinical benefit in urothelial carcinoma; however, emerging evidence suggests that its efficacy may differ between bladder cancer and upper tract urothelial carcinoma (UTUC), potentially reflecting differences in genomic profiles and the tumor microenvironment (TME). This study aimed to evaluate the association between key oncogenic mutations and the TME characteristics in UTUC, with a particular focus on the impact of neoadjuvant chemotherapy (NAC).  Methods: We analyzed tumor specimens from 32 patients who underwent nephroureterectomy for UTUC. Patients were categorized into NAC and non-NAC groups. Oncogenic mutations (TP53, FGFR3, and RAS) were assessed in all patients, and immune cell densities (CD3+, CD4+, CD8+, Foxp3+, and CD204+) in intratumoral and peritumoral regions were quantified using multiplex fluorescent immunohistochemistry.  Results: TP53, FGFR3, and RAS mutations were identified in 29%, 31%, and 34% of patients, respectively. NAC was administered to 22% of patients. The NAC group demonstrated significantly higher densities of intratumoral CD4+ T cells (p = 0.0201) and a trend toward increased CD8+ T cells (p = 0.0614). Among patients with TP53 mutations, NAC was associated with significantly higher intratumoral CD4+ T cell density (p = 0.0369) compared without NAC. In contrast, FGFR3-mutant tumors exhibited consistently low immune cell infiltration, irrespective of NAC status.  Conclusions: TP53-mutant tumors from patients who received NAC were associated with higher intratumoral CD4⁺ T cell density, whereas FGFR3-mutant tumors exhibited persistently low immune-cell infiltration irrespective of NAC exposure. These findings highlighted distinct mutation-associated TME features in UTUC.  Supplementary Information: The online version contains supplementary material available at https://doi.org/10.1007/s00262-026-04500-1.
SN  - 0340-7004
SN  - 1432-0851
ER  -