Tracking circulating PD-L1-positive cells to monitor the outcome of patients with gastric cancer receiving anti-HER2 plus anti-PD-1 therapy

Sep 28, 2026

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Dual blockade of HER2 and PD-1/PD-L1 is a promising regimen for HER2-positive gastric cancer, where PD-L1 combined positive score may predict benefit. Circulating tumor and endothelial cells enable dynamic assessment of PD-L1 expression, but the biomarker value of PD-L1-positive CTCs/CECs for combination efficacy is unclear. This study profiles PD-L1 expression and heterogeneous karyotypes using SE-iFISH in 72 advanced GC patients, linking baseline PD-L1+CTCs and post-treatment PD-L1+CECs to progression-free survival and resistance-associated subtypes.

LanguageEnglish

CategoryHealthcare

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Pages13

Reading Time33 min

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Abstract

Introduction

Human Cell (2024) 37:258–270 [https://doi.org/10.1007/s13577-023-00990-8](https://doi.org/10.1007/s13577-023-00990-8) Tracking circulating PD‑L1‑positive cells to monitor the outcome of patients with gastric cancer receiving anti‑HER2 plus anti‑PD‑1 therapy Xiaoyi Chong1 · Yanyan Li1 · Jialin Lu1 · Xujiao Feng1 · Yilin Li1 · Xiaotian Zhang1 Received: 14 May 2023 / Accepted: 29 September 2023 / Published online: 27 October 2023 © The Author(s) 2023 Abstract Dual blockade of HER2 and PD-1/PD-L1 is the most promising regimen for HER2-positive patients with gastric cancer (GC); PD-L1 combined positive score, rather than HER2 status, indicates potential benefit. Circulating tumor cells (CTCs) and circulating endothelial cells (CECs) derived from the tumor microenvironment provide platforms for the dynamic evaluation of PD-L1 expression. Whether PD-L1 positive CTCs/CECs (PD-L1+CTCs/CECs) can serve as biomarkers for evaluating the efficacy of combination therapy remains unknown. Therefore, this study investigated PD-L1 expression and heterogeneous karyotypic features of CTCs/CECs and their involvement in the clinical response to treatment in 72 patients with advanced GC by applying a pre-established surface molecule-independent subtraction enrichment (SE)-iFISH strategy. In the captured PD-L1 positive cells, there were 42 . 80% and 57.20% of CTCs and CECs, respectively. PD-L1+ CTCs were pre-therapeutically detected in 0%(0/11) of HER2-negative patients and 14.75%(9/61) of HER2-positive patients. The presence of baseline PD-L1+CTCs was relevant to inferior prognosis (mPFS: 14.40 months vs 5.00 months, P = 0.065); post-treatment PD-L1+ CECs were associated with longer irPFS (immunotherapeutic-related PFS) (mPFS: 15.57 months vs 6.73 months, P = 0.053) . Further dynamic karyotype-based profiling of PD-L1+ CTCs/CECs indicated that multiploidy and triploidy were the dominant subtypes of baseline PD-L1+ CTCs, and that triploidy was specifically associated with therapeutic resistance. Intratherapeutically detected multiploid PD-L1+ CECs demonstrated a superior clinical response; triploidy and tetraploidy contributed to acquired resistance. The karyotypic features of PD-L1+CTCs/CECs should be dynamically profiled in patients with GC treated with anti-HER2 plus anti-PD-1 therapy. Triploid-PD-L1+ CTCs and multiploid-PD-L1+ CECs are potential indicators of therapeutic response. Keywords HER2 · PD-L1 · Gastric cancer · CTCs · CECs · Karyotype shifting · Liquid biopsy · SE-iFISH Xiaoyi Chong, Yanyan Li, and Jialin Lu have contributed equally to this work. * Yilin Li[liyilin@bjcancer.org](liyilin@bjcancer.org) * Xiaotian Zhang [zhangxiaotianmed@163.com](zhangxiaotianmed@163.com) 1 Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Department of Gastrointestinal Oncology, Peking University Cancer Hospital and Institute, Fu-Cheng Road 52, Hai-Dian District, Beijing 100142, China Introduction Gastric cancer (GC) is the most common worldwide malignancy with high morbidity and mortality rates [1] . Human epidermal growth factor receptor-2 (HER2) was known as a member of the tyrosine kinase receptor family. Overexpression of HER2 leads to the formation of its various dimers, activation of MAPK, PI3K, JAK–STAT3, and PKC pathways evoking malignant development and tumor progression. Approximately 13% of advanced GC patients are histopathologically positive for human epidermal growth factor receptor-2 (HER2) [2] . An open label, international, phase 3, randomized-controlled trial (ToGA) enrolled 594 HER2-positive gastric or gastroesophageal junction adenocarcinoma patients indicated that compared with chemotherapy alone, trastuzumab (a monoclonal antibody against HER2) plus chemotherapy significantly improved patients survival (mOS: 11.1 moths vs 13.8 moths, p = 0.0046) . Since then, trastuzumab plus chemotherapy became the standard 1stline therapy for HER2-positive gastric or gastroesoph

FAQs

Why focus on PD-L1 rather than HER2 status in gastric cancer therapy?

The study states that PD-L1 combined positive score indicates potential benefit for HER2-positive gastric cancer. It also notes the association between HER2 and PD-L1 expression remains unclear, supporting the need for ongoing PD-L1 evaluation.

How were PD-L1-positive circulating cells detected in the study?

The authors used a pre-established surface molecule-independent subtraction enrichment (SE)-iFISH strategy to profile PD-L1 expression and heterogeneous karyotypic features in CTCs and CECs.

What karyotype features were linked to resistance or clinical response?

Multiploidy and triploidy dominated baseline PD-L1+ CTC subtypes, with triploidy associated with therapeutic resistance. Intratherapeutically detected multiploid PD-L1+CECs showed a superior clinical response, while triploidy and tetraploidy contributed to acquired resistance.

Sep 28, 2026

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