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Preferential B cell differentiation by combined immune checkpoint blockade for renal cell carcinoma is associated with clinical response and autoimmune reactions

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Abstract

Combined immune checkpoint blockade (ICB) is effective therapy for renal cell carcinoma (RCC). However, the dynamic changes in circulating B cells induced by combined ICB have not been clarified. The present study prospectively examined 22 patients scheduled to receive ICB for unresectable or metastatic RCC between March 2018 and August 2021. Eleven patients received combined therapy with anti-PD-1 (nivolumab) and anti-CTLA-4 (ipilimumab), and the other 11 patients received nivolumab monotherapy. Comprehensive phenotypes of circulating immune cells obtained prior to and after ICB therapy were analyzed by flow cytometry. Although the proportion of naïve B cells among total B cells was significantly decreased, that of switched memory B cells was significantly increased after combined therapy. In responders, the proportion of B cells among peripheral blood mononuclear cells was significantly higher prior to ICB therapy, and the proportion of switched memory B cells among total B cells tended to increase after ICB therapy. Of note, the proportion of plasmablasts among total B cells was significantly increased after ICB therapy in patients who developed severe immune-related adverse events (irAEs), and the proportion of B cells among peripheral blood decreased significantly. Furthermore, in four of five patients who developed immune-related hypophysitis following combined therapy, anti-pituitary antibody was detected in the serum. These results suggested that immune-related hypophysitis was closely related to the increase in circulating plasmablasts. Collectively, this study suggests that combined ICB promotes the differentiation of B cell populations, which is associated with efficient tumor suppression and development of irAEs.

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Acknowledgements

We appreciate the technical assistance provided by the Department of Morphology Core Unit, Kyushu University Hospital, Fukuoka, Japan.

Funding

This study was supported by JSPS KAKENHI Grant Number JP20K08311.

Author information

Authors and Affiliations

  1. Department of Medicine and Biosystemic Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Koki Uehara, Kenro Tanoue & Koichi Akashi

  2. Department of Hematology, Oncology and Cardiovascular Medicine, Kyushu University Hospital, Fukuoka, Japan

    Kyoko Yamaguchi, Mamoru Ito, Kenji Tsuchihashi & Hiroshi Ariyama

  3. Department of Internal Medicine, Kyushu University Beppu Hospital, Beppu, Japan

    Hirofumi Ohmura

  4. Department of Medical Oncology, Hamanomachi Hospital, Fukuoka, Japan

    Yuzo Matsushita, Risa Tanaka & Hitoshi Kusaba

  5. Department of Medical Oncology, National Hospital Organization Kyushu Medical Center, Fukuoka, Japan

    Shingo Tamura

  6. Department of Hematology and Oncology, Japan Community Health Care Organization Kyushu Hospital, Kitakyushu, Japan

    Hozumi Shimokawa

  7. Department of Oncology and Social Medicine, Graduate School of Medical Sciences, Kyushu University, 3-1-1 Maidashi, Higashi-Ku, Fukuoka, 812-8582, Japan

    Taichi Isobe & Eishi Baba

  8. Department of Medical Oncology, Fukuoka Wajiro Hospital, Fukuoka, Japan

    Yoshihiro Shibata

  9. Department of Anatomic Pathology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan

    Hidetaka Yamamoto & Yoshinao Oda

Authors
  1. Koki Uehara
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  2. Kenro Tanoue
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  4. Hirofumi Ohmura
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Contributions

KU designed the study, performed the experiments, and analyzed all the data. KTa, KY, and HO assisted with the experiments. YM, ST, HS, YS, and RT treated the enrolled patients and collected the clinical data. HY and YO provided pituitary specimens. All authors discussed the data. KU, KTa, KY, and EB wrote the manuscript. All authors participated in revision of the manuscript.

Corresponding author

Correspondence to Eishi Baba.

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Conflict of interest

KTa received honoraria from Ono Pharmaceutical. KY received honoraria from Ono Pharmaceutical and Chugai Pharmaceutical. HO received honoraria from Chugai Pharmaceutical. YM received honoraria from Kyowa Kirin. KTu received Ono Pharmaceutical and Taiho Pharmaceutical. ST received honoraria from Bayer, Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Merck, Daiichi-Sankyo, LSI Medience, and MSD. HS received honoraria from Ono Pharmaceutical, Eli Lilly, Merck. YS received honoraria from Eli Lilly, Daiichi-Sankyo and Kyowa Kirin. HK received honoraria from Chugai Pharmaceutical. HY received honoraria from AstraZeneca, Bayer, Chugai Pharmaceutical Novartis Pharmaceutical. KA received honoraria from BMS, Ono Pharmaceutical, Janssen Pharmaceutical, Chugai Pharmaceutical, Kyowa Kirin, AbbVie GK, and Eisai; and research grants from Chugai Pharmaceutical, Kyowa Kirin, AbbVie GK, Asahi-Kasei, and Takeda Pharmaceutical. EB received honoraria from Ono Pharmaceutical, Chugai Pharmaceutical, Eli Lilly, Taiho Pharmaceutical, Merck, Sanofi, MSD, Eisai, and Daiichi-Sankyo; and research grants from Taiho Pharmaceutical, Chugai Pharmaceutical, and Eli Lilly. The other authors have no competing interests.

Ethics approval

This study was approved by the Ethical Committee of Kyushu University Hospital (no. 29-348). Written informed consent was obtained from all patients prior to enrollment in the study.

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Uehara, K., Tanoue, K., Yamaguchi, K. et al. Preferential B cell differentiation by combined immune checkpoint blockade for renal cell carcinoma is associated with clinical response and autoimmune reactions. Cancer Immunol Immunother 72, 3543–3558 (2023). https://doi.org/10.1007/s00262-023-03505-4

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