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Effect of HLA genotype on intravesical recurrence after bacillus Calmette–Guérin therapy for non-muscle-invasive bladder cancer

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Abstract

The intravesical administration of bacillus Calmette–Guérin (BCG) is widely used to control the intravesical recurrence of non-muscle-invasive bladder cancer (NMIBC). This study aimed to reveal the effects of zygosity on human leukocyte antigen (HLA) genes and individual HLA genotypes on intravesical recurrence after intravesical BCG therapy for NMIBC. This study included Japanese patients who had received intravesical BCG for NMIBC. HLA genotyping of HLA-A, B, C, and DRB1 was performed. The effect of HLA zygosity and HLA genotype on intravesical recurrence was evaluated. Among 195 patients, those homozygous for the HLA-B supertype were more likely than those heterozygous for the HLA-B supertype to experience intravesical recurrence by univariate analysis (hazard ratio [HR], 95% confidence interval [CI]; 1.87, 1.14–3.05, P = 0.012) and multivariate analysis (HR, 95% CI; 2.26, 1.02–5.01, P = 0.045). Patients with B07 or B44 had a decreased risk of intravesical recurrence by univariate analysis (HR, 95% CI; 0.43, 0.24–0.78, P = 0.0056) and multivariate analysis (HR, 95% CI; 0.36, 0.16–0.82, P = 0.016). This study suggests the importance of the diversity and specificity of HLA-B loci in the antitumor effect of BCG immunotherapy for NMIBC. These findings may contribute to the delineation of risk strata for BCG therapy and improve the medical management of NMIBC.

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Acknowledgements

We thank Ms. Yoko Mitobe, Ms. Yukiko Sugiyama, Ms. Noriko Hakoda, and Ms. Eriko Gunshima for technical assistance. We thank J. Ludovic Croxford, Ph.D., from Edanz Group (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was partly supported by grants (Nos. 21K06592, 19K18551) from the Japan Society for the Promotion of Science, Tokyo, Japan, and the Nakatomi Foundation, Tokyo, Japan.

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Authors and Affiliations

  1. Department of Urology, Graduate School of Medicine, Akita University, Akita, 010-8543, Japan

    Mizuki Kobayashi, Shintaro Narita, Kazuyuki Numakura & Tomonori Habuchi

  2. Center for Kidney Disease and Transplantation, Akita University Hospital, Akita, 010-8543, Japan

    Nobuhiro Fujiyama

  3. Department of Urology, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-ku, Fukuoka, 812–8582, Japan

    Tokiyoshi Tanegashima, Shohei Ueda, Ario Takeuchi, Masatoshi Eto & Masaki Shiota

  4. Department of Urology, Graduate School of Medicine, Yamaguchi University, Ube, 755–8505, Japan

    Yoshiaki Yamamoto & Hideyasu Matsuyama

  5. Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, 807–8556, Japan

    Naohiro Fujimoto

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  1. Mizuki Kobayashi
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Contributions

MS and SN contributed to conception and design. MK, NF, TT, SN, and MS collected and assembled data. SN, YY, NF, AT, KN, and MS provisioned study material or patients. TT, SU, and MS analyzed and interpreted data. MS contributed to manuscript writing. TT and SU contributed to co-writing the manuscript. NF, SN, AT, KN, TH, HM, and ME critically reviewed the manuscript. ME contributed to supervision. All authors reviewed the manuscript and gave final approval of the manuscript.

Corresponding author

Correspondence to Masaki Shiota.

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Conflict of interest

Shintaro Narita received honoraria from Janssen Pharmaceutical, Bayer Yakuhin, AstraZeneca, Takeda Pharmaceutical, Sanofi, and Astellas Pharma. Tomonori Habuchi received honoraria from Janssen Pharmaceutical, Takeda Pharmaceutical, Astellas Pharma, Daiichi Sankyo, AstraZeneca, Sanofi, and Bayer Yakuhin, and research funding support from Takeda Pharmaceutical, Astellas Pharma, Daiichi Sankyo, Sanofi, and Bayer Yakuhin. Masatoshi Eto received honoraria from Ono Pharmaceutical, Takeda Pharmaceutical, Novartis Pharma, Pfizer, Bristol-Myers Squibb, Janssen Pharmaceutical, MSD, and Merck Biopharma, and research funding support from Sanofi, Bayer Yakuhin, Astellas Pharma., Ono Pharmaceutical., and Takeda Pharmaceutical. Masaki Shiota received honoraria from Janssen Pharmaceutical, AstraZeneca, and Astellas Pharma, and research funding support from Daiichi Sankyo.

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The study was conducted under review board at Kyushu University (727-01).

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Written informed consent was obtained from all patients.

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Kobayashi, M., Fujiyama, N., Tanegashima, T. et al. Effect of HLA genotype on intravesical recurrence after bacillus Calmette–Guérin therapy for non-muscle-invasive bladder cancer. Cancer Immunol Immunother 71, 727–736 (2022). https://doi.org/10.1007/s00262-021-03032-0

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