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Molecular Diagnostics

Pretreatment tumour immune microenvironment predicts clinical response and prognosis of muscle-invasive bladder cancer in the neoadjuvant chemotherapy setting

British Journal of Cancer volume 126, pages 606–614 (2022)Cite this article

Subjects

Abstract

Background

We examined the relationship between the tumour microenvironment and the clinical efficacy of neoadjuvant chemotherapy in patients with cT2-4aN0M0 bladder cancer using multiplex fluorescence immunohistochemistry.

Methods

The study retrospectively evaluated 51 patients who underwent radical cystectomy following neoadjuvant chemotherapy for cT2-4aN0M0 muscle-invasive bladder cancer. Patients were divided into responders (<pT2) and non-responders (≥pT2). We assessed the density of each immune cell type in intratumoural and peritumoural areas in both groups via multiplex fluorescence immunohistochemical analysis.

Results

The median age was 69 years; 39 patients were male. Twelve (23.5%), 17 (33.3%), 10 (19.7%) and 12 (23.5%) patients were pT0, pT1, pT2 and ≥pT3, respectively. Responders had a significantly higher 5-year cancer-specific survival rate (96.6%) than non-responders (48.4%; p = 0.0018). CD8+ T cell (p = 0.0056) and CD204+ cell (p = 0.0394) densities were significantly higher in the intratumoural area in non-responders than in responders. Patients with higher CD204+ cell densities in cancerous areas had worse prognosis.

Conclusions

This comprehensive analysis of the immune microenvironment of a muscle-invasive bladder cancer specimen revealed that preexisting tumour-infiltrating proliferating CD8+ T cells and CD204+ cells are indicators of the response to neoadjuvant chemotherapy and that CD204+ cells can be considered an unfavourable prognostic factor in these patients.

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Fig. 1: Assessment of tumor immune microenvironment.
Fig. 2: Correlation of intratumoral immune cells in pre-NAC tissues.
Fig. 3: Changes in intratumoral immune cells pre- and post-NAC treatment.
Fig. 4: Assessment of intratumoral CD8+ T cell function.
Fig. 5: Progression-free survival and cancer-specific survival in patients with high and low infiltration of CD8+ T cell and CD204+ cell.

Data availability

All data supporting the results are presented with results and in the figures.

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Acknowledgements

The authors would like to thank all patients and their families. They also would like to thank Enago (www.enago.jp) for the English language review.

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Authors and Affiliations

  1. Department of Urology, Iwate Medical University School of Medicine, Iwate, 028-3695, Japan

    Daiki Ikarashi, Takashi Tsuyukubo, Shigekatsu Maekawa, Renpei Kato, Yoichiro Kato & Wataru Obara

  2. Division of Cancer Immunotherapy Development, Advanced Medical Development Center, The Cancer Institute Hospital of Japanese Foundation for Cancer Research, Tokyo, 135-8550, Japan

    Daiki Ikarashi, Shigehisa Kitano, Makiko Yamashita & Hidenori Mizugaki

  3. Division of Cancer Immunotherapy, Exploratory Oncology Research and Clinical Trial Center, National Cancer Center, Chiba, 277-0872, Japan

    Daiki Ikarashi, Kazumasa Takenouchi, Takayuki Nakayama & Tetsuya Nakatsura

  4. Department of Human Pathology, Juntendo University School of Medicine, Tokyo, 113-0033, Japan

    Hiroko Onagi & Asumi Sakaguchi

  5. Department of Pathology, Iwate Medical University School of Medicine, Iwate, 028-3695, Japan

    Tamotsu Sugai

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Contributions

Study conception and design: DI, SK and WO; data acquisition and analysis: DI, TT, KT, MY, HM, SM, RK and YK; drafting the manuscript and figures: DI, HO and AS; reviewing the manuscript: SK, TN, TS, TT and WO. All authors have read and approved the final draft for submission.

Corresponding author

Correspondence to Shigehisa Kitano.

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Competing interests

SK reports personal fees from Astra Zeneca, grants and personal fees from Chugai, personal fees from Pfizer, grants and personal fees from Boehringer Ingelheim, personal fees from Taiho, personal fees from Novartis, grants and personal fees from Daiichi-Sankyo, personal fees from MSD, personal fees from Sumitomo Dainippon Pharma, grants and personal fees from Eisai, grants from Astellas, grants from Gilead Sciences, grants and personal fees from Ono Pharmaceutical Co., Ltd, personal fees from Bristol-Myers Squibb, grants and personal fees from REGENERON, personal fees from AYUMI Pharmaceutical Corporation, personal fees from Rakuten Medical, grants from PACT Pharma, grants from Takara Bio Inc., personal fees from GSK, personal fees from ImmuniT Research Inc., grants and personal fees from Ono Pharmaceutical Co., Ltd, personal fees from PMDA (Pharmaceuticals and Medical Devices Agency), grants from AMED (Japan Agency for Medical Research and Development) and grants from JSPS (Japan Society for the Promotion of Science), outside the submitted work. The remaining authors declare no competing interests.

Ethics approval and consent to participate

The study was conducted in accordance with the principles of the Declaration of Helsinki. The human ethics board of each institution approved this study and written informed consent was obtained from all patients prior to enrolment (Iwate Medical University; Protocol No. 2019-083, National Cancer Center Hospital East; Protocol No. 2019-194).

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Ikarashi, D., Kitano, S., Tsuyukubo, T. et al. Pretreatment tumour immune microenvironment predicts clinical response and prognosis of muscle-invasive bladder cancer in the neoadjuvant chemotherapy setting. Br J Cancer 126, 606–614 (2022). https://doi.org/10.1038/s41416-021-01628-y

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