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Soluble PD-L1 as a diagnostic and prognostic biomarker in resectable gastric cancer patients

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Abstract

Background

In this study, we compared programmed death-ligand 1 (PD-L1) expression in primary tissue samples and its soluble form (sPD-L1) concentration in matched preoperative plasma samples from gastric cancer patients to understand the relationship between tissue and plasma PD-L1 expression and to determine its diagnostic and prognostic value.

Methods

PD-L1 expression in tissue was assessed by immunohistochemistry and enzyme-linked immunosorbent assay (ELISA), and sPD-L1 concentration in plasma was quantified by ELISA. The levels of the CD274 gene, which encodes for PD-L1 protein, were examined as part of bulk tissue RNA-sequencing analyses. Additionally, we evaluated the association between sPD-L1 levels and various laboratory parameters, disease characteristics, and patient outcomes.

Results

GC patients had significantly higher levels of sPD-L1 in their plasma (71.69 pg/mL) compared to healthy controls (35.34 pg/mL) (p < 0.0001). Moreover, sPD-L1 levels were significantly correlated with tissue PD-L1 protein, CD274 mRNA expression, larger tumor size, advanced tumor stage, and lymph node metastasis. Elevated sPD-L1 levels (> 103.5 ng/mL) were associated with poor overall survival (HR = 2.16, 95%CI 1.15–4.08, p = 0.017). Furthermore, intratumoral neutrophil and dendritic cell levels were directly correlated with plasma sPD-L1 concentration in the GC patients.

Conclusions

sPD-L1 was readily measurable in GC patients, and its level was associated with GC tissue PD-L1 expression, greater inflammatory cell infiltration, disease progression, and survival. Thus, sPD-L1 may be a useful minimally invasive diagnostic and prognostic biomarker in GC patients.

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Funding

This work was supported by a grant from the Ministry of Research, Innovation, and Digitization, CNCS/CCCDI–UEFISCDI, project number PN-III-P4-ID-PCCF-2016-0158 (contract PCCF 17/2018), within PNCDI III (to IP) and contract number 33PFE/30.12.2021 (to SD). SK was supported by a JSPS KAKENHI Grant number 18K08717, by the Cooperative Research Project Program of Joint Usage/Research Center at the Institute of Development, Aging, and Cancer, Tohoku University, and grants from the Gastrointestinal Cancer Project funded by Nakayama Cancer Research Institute. DGD’s research is supported by US National Institutes of Health grants R01CA260857, R01CA254351, R01CA247441, R03CA256764, and P01CA261669, and by Department of Defense PRCRP grants W81XWH-19-1-0284 and W81XWH-21-1-0738. The funders had no role in the study's design; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.

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Author notes

  1. Mihaela Chivu-Economescu and Vlad Herlea have contributed equally.

Authors and Affiliations

  1. Department of Cellular and Molecular Pathology, Stefan S. Nicolau Institute of Virology, 030304, Bucharest, Romania

    Mihaela Chivu-Economescu, Laura Necula, Lilia Matei, Denisa Dragu, Ana-Iulia Neagu, Coralia Bleotu & Carmen C. Diaconu

  2. Department of Pathology, Fundeni Clinical Institute, 022328, Bucharest, Romania

    Vlad Herlea, Catalin Pechianu & Alexandru Procop

  3. Center of Digestive Diseases and Liver Transplantation, Fundeni Clinical Institute, 022328, Bucharest, Romania

    Simona Dima & Irinel Popescu

  4. Center of Excellence for Translational Medicine, Fundeni Clinical Institute, 022328, Bucharest, Romania

    Simona Dima, Andrei Sorop & Irinel Popescu

  5. Edwin L. Steele Laboratories for Tumor Biology, Department of Radiation Oncology, Harvard Medical School and Massachusetts General Hospital, Cox-724, 100 Blossom St., Boston, MA, 02114, USA

    Shuji Kitahara & Dan G. Duda

  6. Carol Davila University of Medicine and Pharmacy, 050474, Bucharest, Romania

    Simona Dima

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  1. Mihaela Chivu-Economescu
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Contributions

Conceptualization, MC-E, SD, IP, and DGD. Material preparation and data collection, SD and IP. Tissue samples selection and IHC analyses, VH, CP, AP, SK, and DGD. MSI analysis, LM, DD, and CCD. RNA-seq analyses, AS. sPD-L1 testing in plasma and PD-L1 testing tissue, LN, A-IN, SK, and CB. Formal analysis and investigation, original draft preparation, MC-E. Funding, IP and DGD. Writing–review & editing, SD, SK, and DGD. All authors have read, edited, and approved the final version of the manuscript.

Corresponding author

Correspondence to Dan G. Duda.

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Conflict of interest

DGD received consultant fees from Innocoll Pharmaceuticals and research grants from Exelixis, Bayer, BMS, and Surface Oncology. No reagents or funding from these companies were used in this study. The other authors declare no conflict of interest.

Ethical approval

All procedures performed in studies involving human participants were in accordance with the ethical standards of the institutional research committee and with the 1964 Helsinki declaration and its later amendments or comparable ethical standards. This article does not contain any studies with animals performed by any of the authors.

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Informed consent was obtained from all individual participants included in the study.

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Chivu-Economescu, M., Herlea, V., Dima, S. et al. Soluble PD-L1 as a diagnostic and prognostic biomarker in resectable gastric cancer patients. Gastric Cancer 26, 934–946 (2023). https://doi.org/10.1007/s10120-023-01429-7

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