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The effect of human leukocyte antigen genotype on survival in advanced prostate cancer treated with primary androgen deprivation therapy: the KYUCOG-1401-A study

Prostate Cancer and Prostatic Diseases (2024)Cite this article

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Abstract

Background

Immune editing, in which human leukocyte antigens (HLA) have critical roles, has been suggested to shape the landscape of human cancer. This study prospectively investigated whether HLA gene zygosity is associated with the prognosis of primary androgen deprivation therapy in advanced prostate cancer.

Methods

KYUCOG-1401-A was conducted in conjunction with a prospective clinical trial (KYUCOG-1401). Among the patients enrolled in KYUCOG-1401 and treated with primary androgen deprivation therapy, only Japanese patients were included. HLA genotypes of HLA-A, B, C, DRB1, DQB1, and DPB1 were determined. The effect of divergence of HLA genotypes on time to progression, prostate cancer-specific survival, and overall survival was evaluated.

Results

Among 127 patients, homozygosity for HLA-DRB1 (HR, 95% CI; 4.05, 1.54–10.7, P = 0.0047) and HLA-DQB1 (HR, 95% CI; 3.75, 1.47–9.58, P = 0.0058) was associated with an increased risk of prostate cancer-specific mortality. Patients with higher HLA evolutionary divergence scores at HLA-DQB1 (HR, 95% CI; 0.90, 0.82–0.97, P = 0.0093) had lower risks of prostate cancer-specific mortality. Androgen-responsive gene sets were upregulated in CD4low and CD8low tumors in the prostate cancer cohort, but not in the bladder and kidney cancer cohorts.

Conclusions

This study suggested that the diversity of HLA-II loci including HLA-DRB1 and HLA-DQB1 plays an important role in advanced prostate cancer survival, contributing to improved risk stratification in advanced prostate cancer. Moreover, it was shown that CD4+ T cells play an important role in androgen deprivation therapy, suggesting that immunotherapy targeting CD4+ T cells is promising for prostate cancer.

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Fig. 1: Kaplan–Meier survival analysis of prostate cancer-specific survival stratified by zygosity of HLA alleles.
Fig. 2: Kaplan–Meier survival analysis of prostate cancer-specific survival stratified by zygosity of HLA-I/II locus.
Fig. 3: Gene expression signatures of CD4low and CD4high tumors in prostate cancer.
Fig. 4: Schematic representation of the role of HLA-II during androgen-deprivation therapy for prostate cancer.

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Data availability

The data that support the findings of this study are available from the corresponding author upon reasonable request.

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Acknowledgements

We would like to thank Ms. Noriko Hakoda and Ms. Eriko Gunshima for their technical assistance. We particularly thank Dr. Kaori Yasuda and Dr. Atsushi Doi (Cell Innovator, Fukuoka, Japan) for their excellent guidance in the HLA analysis. We also appreciate the Clinical Research Support Center Kyushu (CReS Kyushu) for their secretarial assistance and supportive assistance. We are grateful to the patients who volunteered to participate in this trial, as well as the following KYUCOG-1401-A investigators and trial staff: Noriaki Tokuda at Saga-ken Medical Centre Koseikan (Saga), Kentaro Kuroiwa at Miyazaki Prefectural Miyazaki Hospital (Miyazaki), Kazuya Kawahara at Kawahara Nephro-Urology Clinic (Aira), Motonobu Nakamura at National Hospital Organization Kyushu Cancer Center (Fukuoka), Ken Goto at Japanese Red Cross Fukuoka Hospital (Fukuoka), Sumitaka Mitsu at Kagoshima Prefectural Oshima (Amami), Masafumi Nagano at Fujimoto General Hospital (Miyakonojo), Naotaka Sakamoto at National Hospital Organization Kyushu Medical Center (Fukuoka), Youji Doman at Saiseikai Sendai Hospital (Satsumasendai), Hironobu Wakeda at Chiyoda Hospital (Hyuga), Yasufumi Nabekura at Kumamoto Urological Hospital (Kumamoto), Kohei Mizuma at National Hospital Organization Ibusuki Medical Center (Ibusuki), and Hisato Inatomi at Munakata Suikokai General Hospital (Fukutsu). Finally, we thank H. Nikki March, PhD, from Edanz (https://jp.edanz.com/ac) for editing a draft of this manuscript.

Funding

This work was supported by a JSPS KAKENHI grant (17K11145), the Japanese Urological Association, Takeda Science Foundation, and Shinnihon Foundation of Advanced Medical Treatment Research to M.S. KYUCOG-1401 (UMIN000014243, jRCTs071180035) was supported by Astellas Pharma.

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Authors and Affiliations

  1. Department of Urology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Masaki Shiota, Tokiyoshi Tanegashima & Masatoshi Eto

  2. Department of Urology, Graduate School of Medical and Dental Sciences, Kagoshima University, Kagoshima, Japan

    Shuichi Tatarano

  3. Department of Urology, Faculty of Medicine, Miyazaki University, Miyazaki, Japan

    Toshiyuki Kamoto

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

    Hideyasu Matsuyama

  5. Department of Urology, Graduate School of Biomedical Sciences, Nagasaki University, Nagasaki, Japan

    Hideki Sakai

  6. Department of Urology, School of Medicine, Kurume University, Kurume, Japan

    Tsukasa Igawa

  7. Department of Urology, Kumamoto University, Kumamoto, Japan

    Tomomi Kamba

  8. Department of Urology, School of Medicine, University of Occupational and Environmental Health, Kitakyushu, Japan

    Naohiro Fujimoto

  9. Department of Urology, Harasanshin Hospital, Fukuoka, Japan

    Akira Yokomizo & Seiji Naito

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  1. Masaki Shiota
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Contributions

Concept and design: MS and ME; Acquisition, analysis, or interpretation of data: MS and TT; Drafting of the manuscript: MS; Critical revision of the manuscript: All authors; Statistical analysis: MS; Obtaining funding: ME; Administrative, technical, or material support: All authors; Supervision: ME.

Corresponding author

Correspondence to Masaki Shiota.

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Competing interests

MS received honoraria from Janssen Pharmaceutical, AstraZeneca, Astellas Pharma, Sanofi, and Bayer and research funding support from Daiichi Sankyo. TK received research funding support from Janssen Pharmaceutical, Astellas Pharma, Shin Nippon Biomedical Laboratories, Ono Pharmaceutical, Bayer, Sanofi, and Takeda Pharmaceutical. HM received honoraria from Janssen Pharmaceutical, AstraZeneca, Astellas Pharma, Bayer, Chugai Pharmaceutical, and Merck and research funding support from Janssen Pharmaceutical, Takeda Pharmaceutical, and Kyowa Kirin. HS received honoraria from Takeda Pharmaceutical and Astellas Pharma. TI received honoraria from Janssen Pharmaceutical and Astellas Pharma. TK received honoraria from Takeda Pharmaceutical, AstraZeneca and Merck. AY received honoraria from Janssen Pharmaceutical and Astellas Pharma. ME received honoraria from Takeda Pharmaceutical, Janssen Pharmaceutical, AstraZeneca, and Astellas Pharma and research funding support from Astellas Pharma, Sanofi, and Takeda Pharmaceutical.

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Shiota, M., Tanegashima, T., Tatarano, S. et al. The effect of human leukocyte antigen genotype on survival in advanced prostate cancer treated with primary androgen deprivation therapy: the KYUCOG-1401-A study. Prostate Cancer Prostatic Dis (2024). https://doi.org/10.1038/s41391-024-00808-0

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