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Molecular Diagnostics

Predictive factors for neoadjuvant combined immunotherapy in gastric adenocarcinoma: Focusing on the primitive enterocyte phenotype and PVR

British Journal of Cancer volume 133, pages 255–269 (2025)Cite this article

Subjects

Abstract

Background

Neoadjuvant combined immunotherapy has provided more treatment options for patients with gastric adenocarcinoma (GA). However, some GA patients, especially those with primitive enterocyte phenotype (GAPEP) show a poor response to immunotherapy, even with positive PD-L1 expression.

Method

We enrolled multiple cohorts from our center and utilized public data to identify the predictive factors and explore the immunosuppressive features of GAPEP by multi-omics methods.

Results

Forty-seven patients with neoadjuvant combined immunotherapy were enrolled. After testing, we found PD-L1 combined positive score (CPS) ≥ 50 in biopsy tissues was significantly associated with major pathological response (MPR) (P = 0.04). RNA testing and immunohistochemical staining highlighted the cytotoxicity-associated markers (GZMA and PRF1) as the predictors to better response. Notably, GAPEP patients demonstrated resistance to therapy and exhibited worse survival outcomes. Our own and public bulk/single-cell transcriptomic analyses identified PVR as a predictor of treatment resistance and as an important immune suppressor, especially in GAPEP. Cell interaction analyses, multiple staining, and cell experiments verified the association between GAPEP and PVR.

Conclusion

Cytotoxic markers, especially GZMA and PRF1, could predict the benefit of neoadjuvant combined immunotherapy in GA than PD-L1 CPS, while PVR is a negative predictor, particularly for GAPEP patients.

Highlights

  • IHC staining of cytotoxic markers such as GZMA and PRF1 could better predict ICI benefit in GA than PD-L1 CPS, while positive PVR IHC staining is a negative predictor.

  • GAPEP (GA with the primitive enterocyte phenotype) is more aggressive and more likely to resist immunotherapy.

  • Upregulation of PVR is prevalent in GAPEP, and PVR might be the key factor in promoting the immunosuppressive microenvironment of GAPEP.

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Fig. 1: Characteristics of the tC cohort.
Fig. 2: NanoString mRNA testing results across different cohorts and groups.
Fig. 3: TCGA analysis results in comparing PEP vs. nPEP.
Fig. 4: Shared differential genes and IHC testing.
Fig. 5: Verification in six additional public datasets.
Fig. 6: Single-cell RNA analyses and validation of the relationship between AFP and PVR.

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Data availability

Available. The datasets used and/or analyzed during the current study are available from the corresponding author upon reasonable request.

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Funding

This work was supported by the Chinese Academy of Medical Sciences Innovation Fund for Medical Sciences 2023-I2M-2-004 and 2021-I2M-1-067, the Beijing Hope Run Special Fund (No. LC2021A20) and Beijing Xisike Clinical Oncology Research Foundation (Y-MSDZD2022-0245).

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  1. These authors contributed equally: Bingzhi Wang, Yinong Wang.

Authors and Affiliations

  1. Department of Pathology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Bingzhi Wang, Lei Guo, Hua Zeng, Shuai Wu, Long Wang, Jiali Mu, Na Cheng, Jianming Ying & Liyan Xue

  2. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Yinong Wang

  3. Department of Diagnostic Radiology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Yongjian Zhu

  4. Department of Pancreatic and Gastric Surgery, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing, 100021, China

    Xinxin Shao & Yantao Tian

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Contributions

LX and JY formulated the study concept and design; BW and YW developed the methodology and performed the writing, review and revision of the paper; XS and YT provided the clinical data; HZ, YZ and NC analyzed and interpretated the data and performed statistical analysis; LG, JM, SW and LW provided technical and material support. All authors read and approved the final paper.

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Correspondence to Jianming Ying, Yantao Tian or Liyan Xue.

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Ethical approval was granted by the CICAMS ethics committee prior to commencing this study (No21/105-2776). All methods were carried out in accordance with relevant guidelines and regulations, and informed consent was obtained from all participants.

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Wang, B., Wang, Y., Zhu, Y. et al. Predictive factors for neoadjuvant combined immunotherapy in gastric adenocarcinoma: Focusing on the primitive enterocyte phenotype and PVR. Br J Cancer 133, 255–269 (2025). https://doi.org/10.1038/s41416-025-03031-3

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