Incidence of B-cell Malignancies in Patients with Lung Cancer Receiving PD-1 Blockade Therapy
PURPOSE: Many patients with various cancers have received immune checkpoint inhibitors (ICIs) worldwide since their approval, and novel unexpected complications from their long-term use are apparent. We identified some cases of B cell lymphoma occurring during PD-1 blockade therapy as such unexpected complications. In this study, we aimed to evaluate the incidence of hematological malignancies in patients with lung cancer receiving PD-1 blockade therapy and to elucidate the mechanisms underlying the progression of these malignancies. EXPERIMENTAL DESIGN: We performed immunohistochemical staining on the clinical samples from patients with B cell lymphoma that developed during PD-1 blockade therapy and analyzed large-scale real-world datasets. We further investigated the underlying mechanisms through in vitro and in vivo experiments. RESULTS: A higher incidence of B cell malignancies has been observed in patients with lung cancer treated with PD-1 blockade therapies based on large-scale real-world data analyses (n = 15,670). Our identified lymphomas had a large amount of CD4+ T follicular helper (TFH)-cell infiltration. In addition, PD-1 blockade activated PD-1+ TFH cells, which promoted lymphoma proliferation via the IL-4/IL-4R, IL-21/IL-21R, and CD40L/CD40 axes. Notably, the lymphomas exhibited high expression of IL-4R, IL-21R, and CD40. CONCLUSIONS: Our findings highlight the need for careful monitoring and consideration of the potential B-cell malignancy complications in clinical settings where ICIs are used.
Authors
- Kadoaki Ohashi (ORCID: https://orcid.org/0000-0002-5180-3933)
- Takamasa Ishino (ORCID: https://orcid.org/0000-0002-8601-0677)
- Yoshito Zamami (ORCID: https://orcid.org/0000-0002-7879-423X)
- Shin Morizane (ORCID: https://orcid.org/0000-0003-1374-065X)
- Li zhu
- Youki Ueda (ORCID: https://orcid.org/0000-0002-2627-8524)
- Hirofumi Hamano (ORCID: https://orcid.org/0000-0002-2231-0179)
- Daisuke Ennishi (ORCID: https://orcid.org/0000-0003-4788-2103)
- Toshihiro Koyama (ORCID: https://orcid.org/0000-0002-7755-1754)
- Joji Nagasaki (ORCID: https://orcid.org/0000-0003-0945-5469)
- Toshifumi Ninomiya (ORCID: https://orcid.org/0009-0006-0882-8154)
- Yusuke Naoi
- Tatsuya Nishi (ORCID: https://orcid.org/0009-0003-9568-7262)
- Tomoya Katsuta
- Teruya Morinaga
- Isamu Okamoto (ORCID: https://orcid.org/0000-0002-7587-6096)
- Yosuke Togashi (ORCID: https://orcid.org/0000-0001-9910-0164)
- Caiyang Fang (ORCID: https://orcid.org/0009-0007-2885-7048)
- Sakura Miki (ORCID: https://orcid.org/0009-0005-6832-2166)
- Tomoka Ohki-Ikeda (ORCID: https://orcid.org/0000-0001-6357-4691)
- Yoshinobu Maeda (ORCID: https://orcid.org/0000-0003-1634-5487)
- Wenhao Zhou (ORCID: https://orcid.org/0000-0003-1286-241X)
Institutions
- Kyushu University (JP)
- Okayama University of Science (JP)
- Soai University (JP)
- Okayama University (JP)
- Okayama University Hospital (JP)
- Affiliated Hospital of North Sichuan Medical College (CN)
- Ehime Prefectural Central Hospital (JP)
- Nagoya University (JP)
- Tokyo Metropolitan University (JP)
Publication Details
- Journal
- Clinical Cancer Research
- Published
- 2026-05-18
- DOI
- https://doi.org/10.1158/1078-0432.ccr-25-3406
- Primary Topic
- Cancer Immunotherapy and Biomarkers
- Type
- article
- Field-Weighted Citation Impact
- 0.00
Funders
- Naito Foundation
- Japan Research Foundation for Clinical Pharmacology
- Uehara Memorial Foundation
- Japan Agency for Medical Research and Development
- National Cancer Center Japan
- Wesco Science Foundation
- Nippon Shinyaku
- Ichiro Kanehara Foundation for the Promotion of Medical Sciences and Medical Care
- Kato Memorial Bioscience Foundation
- Kowa Life Science Foundation
- Yasuda Memorial Medical Foundation
- Japan Society for the Promotion of Science
- Japan Science and Technology Agency