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. 2025 Mar 18;16(1):348.
doi: 10.1007/s12672-025-02060-x.

Ki-67 expression in anti-programmed cell death protein-1 antibody-bound CD8+ T cells as a predictor of clinical benefit

Toshiaki Tsurui  1   2   3   4 , Masahiro Hosonuma  1   2   3   4 , Aya Sasaki  1   2   4   5 , Yuuki Maruyama  1   2   4   6 , Yasunobu Amari  2   4   7   8 , Eiji Funayama  2   4   9 , Kohei Tajima  2   10 , Hitoshi Toyoda  1   2   4   11 , Junya Isobe  2   12 , Yoshitaka Yamazaki  4   13 , Yuta Baba  2   14 , Midori Shida  2 , Yuko Udaka  1   4 , Emiko Mura  15 , Risako Suzuki  15 , Nana Iriguchi  15 , Tomoyuki Ishiguro  15 , Yuya Hirasawa  15 , Ryotaro Ohkuma  15 , Masahiro Shimokawa  15 , Hirotsugu Ariizumi  15 , Yutaro Kubota  15 , Atsushi Horiike  15 , Satoshi Wada  15   16 , Atsuo Kuramasu  2 , Mayumi Tsuji  4 , Yuji Kiuchi  1   4 , Takuya Tsunoda  15 , Kiyoshi Yoshimura  17   18
Affiliations

Ki-67 expression in anti-programmed cell death protein-1 antibody-bound CD8+ T cells as a predictor of clinical benefit

Toshiaki Tsurui et al. Discov Oncol. .

Abstract

Aims: Developing predictive biomarkers for immune checkpoint inhibitors (ICIs) is important. Programmed cell death protein-1 (PD-1) receptor occupancy by anti-PD-1 antibodies on circulating T cells varies among patients. However, the association between the exhaustion of these antibody-bound T cells and the clinical efficacy of ICIs remains unknown. Therefore, the present study was aimed at evaluating this association.

Methods: This prospective cohort study included patients with advanced non-small cell lung cancer (NSCLC) and esophageal squamous cell carcinoma (ESCC) who received pembrolizumab therapy. Peripheral blood samples were collected during the second cycle of chemotherapy. We analyzed the relationship between exhaustion markers in pembrolizumab-bound (PB) T cells and clinical response.

Results: A total of 21 patients were analyzed, including 12 patients with NSCLC and 9 patients with ESCC. The expression of Ki-67 in PB-CD8+ TCM and TEM was negatively correlated with both clinical response and overall survival.

Conclusion: The expression of Ki-67 of PB-CD8+ TCM and TEM can serve as a predictive biomarker for the clinical benefit of pembrolizumab therapy. Our study suggests that analyzing antibody-bound T cells could be a novel approach to predict the clinical outcomes of PD-1 blockade therapy.

Keywords: Biomarker; Exhaustion; Immune checkpoint inhibitor; Ki-67; Memory T cells; PD-1/PD-L1 signaling.

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Conflict of interest statement

Declarations. Ethics approval and consent to participate: This study was approved by the Ethics Committee of Showa University School of Medicine (Approval Nos. M2253 and B-2018-022). Informed consent was obtained from all enrolled patients. Informed consent was obtained from all enrolled patients. Competing interests: The authors declare no competing interests.

Figures

Fig. 1
Fig. 1
Correlation between Ki-67 of PB-CD8+TCM and TEM and survival. a Ki-67 of PB-CD8+TCM and PFS. b Ki-67 of PB-CD8+TCM and OS. c Ki-67 of PB-CD8+TEM and PFS. d Ki-67 of PB-CD8+TEM and OS. Each dot represents a sample from each patient. The value of r represents Pearson’s correlation coefficient; PFS progression-free survival, OS overall survival
Fig. 2
Fig. 2
Kaplan–Meier plots showing PFS and OS according to the Ki-67 levels in PB-CD8+CD45RA− T cells (TCM and TEM). a PFS. b OS. PFS progression-free survival, OS overall survival, PB pembrolizumab-bound, TCM central memory T cells, TEM effector memory T cells
Fig. 3
Fig. 3
Ki-67 expression correlates with the degree of T cell exhaustion and apoptosis. a Changes in the expression of Ki-67 in CD8+ T cells with the levels of exhaustion markers. The Dunnett’s test was performed for multiple comparisons. b Comparison of Ki-67 expression between early apoptotic T cells and live cells. The paired t-test was performed to compare the two groups. PD-1, programmed cell death protein 1; TIM-3, T cell immunoglobulin, and mucin domain-3. The asterisks indicate the statistical significance, **p < 0.01. TN triple negative, SP single positive, DP double positive, TP triple positive
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