Principal component analysis of early immune cell dynamics during pembrolizumab treatment of advanced urothelial carcinoma

Teshima,Taro; Teshima,Taro; Kobayashi,Yukari; Kobayashi,Yukari; Kawai,Taketo; Kawai,Taketo; Kushihara,Yoshihiro; Kushihara,Yoshihiro; Nagaoka,Koji; Nagaoka,Koji; Miyakawa,Jimpei; Miyakawa,Jimpei; Akiyama,Yoshiyuki; Akiyama,Yoshiyuki; Yamada,Yuta; Yamada,Yuta; Sato,Yusuke; Sato,Yusuke; Yamada,Daisuke; Yamada,Daisuke; Tanaka,Nobuyuki; Tanaka,Nobuyuki; Tsunoda,Tatsuhiko; Tsunoda,Tatsuhiko; Kume,Haruki; Kume,Haruki; Kakimi,Kazuhiro; Kakimi,Kazuhiro

doi:10.3892/ol.2022.13384

Principal component analysis of early immune cell dynamics during pembrolizumab treatment of advanced urothelial carcinoma

Authors:
- Taro Teshima
- Yukari Kobayashi
- Taketo Kawai
- Yoshihiro Kushihara
- Koji Nagaoka
- Jimpei Miyakawa
- Yoshiyuki Akiyama
- Yuta Yamada
- Yusuke Sato
- Daisuke Yamada
- Nobuyuki Tanaka
- Tatsuhiko Tsunoda
- Haruki Kume
- Kazuhiro Kakimi
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Affiliations: Department of Urology, The University of Tokyo Hospital, Tokyo 113‑8655, Japan, Department of Immunotherapeutics, The University of Tokyo Hospital, Tokyo 113‑8655, Japan, Department of Urology, Keio University School of Medicine, Tokyo 160‑8582, Japan, Department of Biological Sciences, School of Science, The University of Tokyo, Tokyo 113‑0033, Japan
Published online on: June 16, 2022 https://doi.org/10.3892/ol.2022.13384
Article Number: 265
Copyright: © Teshima et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Immune checkpoint inhibitors have been approved as second‑line therapy for patients with advanced urothelial carcinoma (UC). However, which patients will obtain clinical benefit remains to be determined. To identify predictive biomarkers for the pembrolizumab (PEM) response early during treatment, the present study investigated 31 patients with chemotherapy‑resistant recurrent or metastatic UC who received 200 mg PEM intravenously every 3 weeks. Blood was taken just before the first dose and again before the second dose, and the peripheral blood mononuclear cells of all 31 pairs of blood samples were immune phenotyped by flow cytometry. Data were assessed by principal component analysis (PCA), correlation analysis and Cox proportional hazards modeling in order to comprehensively determine the effects of PEM on peripheral mononuclear immune cells. Absolute counts of CD45RA⁺CD27^‑CCR7^‑ terminally differentiated CD8⁺ T cells and KLRG1⁺CD57⁺ senescent CD8⁺ T cells were significantly increased after PEM administration (P=0.042 and P=0.043, respectively). Senescent and exhausted CD4⁺ and CD8⁺ T cell dynamics were strongly associated with each other. By contrast, counts of monocytic myeloid‑derived suppressor cells (mMDSCs) were not associated with other immune cell phenotypes. The results of PCA and non‑hierarchical clustering of patients suggested that excessive T cell senescence and differentiation early during treatment were not necessarily associated with a survival benefit. However, decreased mMDSC counts after PEM were associated with improved overall survival. In conclusion, early on‑treatment peripheral T cell status was associated with response to PEM; however, it was not associated with clinical benefit. By contrast, decreased peripheral mMDSC counts did predict improved overall survival.

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