Plasma extracellular vesicle derived protein profile predicting and monitoring immunotherapeutic outcomes of gastric cancer
Cheng Zhang, Xiaoyi Chong, Fangli Jiang, Jing Gao, Yang Chen, Keren Jia, Meng Fan, Xuan Liu, Jin An, Jian Li, Xiaotian Zhang, Lin Shen, Cheng Zhang, Xiaoyi Chong, Fangli Jiang, Jing Gao, Yang Chen, Keren Jia, Meng Fan, Xuan Liu, Jin An, Jian Li, Xiaotian Zhang, Lin Shen
Abstract
Immune checkpoint inhibitor (ICI)-based immunotherapy brought new hope for gastric cancer (GC) treatment. However, due to the lack of proper biomarkers, patient selection and outcome prediction for GC's immunotherapy remain unsatisfying. In this study, through applying an extracellular vesicle (EV) protein expression array, we assessed the correlation of plasma EV-derived protein spectrum with outcomes of ICI-related therapeutic combinations. Plasma from 112 GC patients received ICI-related therapies were investigated retrospectively/prospectively as three cohorts. We identified four plasma EV-derived proteins (ARG1/CD3/PD-L1/PD-L2) from 42 crucial candidate proteins and combined them as an EV-score that robustly predicting immunotherapeutic outcomes at baseline and dynamically monitoring disease progression along with treatment. High EV-score reflected microenvironmental features of stronger antitumour immunity, characterized by more activated CD8+ T/NK cells, higher TH1/TH2 ratio and higher expressions of IFN-γ/perforin/granzymes in paired peripheral blood, which were verified by dataset analysis and in vivo experiments. EV-score≥1 GC received more therapeutic benefits from ICIs, while EV-score < 1 GC potentially benefited more from ICIs combining HER2-targeted therapies. Collectively, through proposing a plasma EV-score on protein level that powerfully predicting and monitoring GC's immunotherapeutic outcomes, our work facilitated clinical patient selection and decision-makings, and provided mechanistical insights for immunotherapy-related microenvironmental changes and improvements for current ICI-regimens.
Keywords: extracellular vesicle derived protein profile; gastric cancer; immunotherapy; plasma-based liquid biopsy; therapeutic biomarker.
Conflict of interest statement
Meng Fan, Xuan Liu and Jin An are the employees of EVbio Technology Co., Ltd. The remaining authors report no conflict of interest.
© 2022 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals, LLC on behalf of the International Society for Extracellular Vesicles.
Figures
![FIGURE 1](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8971562/bin/JEV2-11-e12209-g003.jpg)
![FIGURE 2](https://www.ncbi.nlm.nih.gov/pmc/articles/instance/8971562/bin/JEV2-11-e12209-g002.jpg)
FIGURE 3
EV‐score dynamically monitored ICI outcomes.…
FIGURE 3
EV‐score dynamically monitored ICI outcomes. (a) Fold changes of EV protein panel and…
FIGURE 4
EV‐score predicted ICI outcomes for…
FIGURE 4
EV‐score predicted ICI outcomes for a prospective validating cohort. (a) The prognostic correlations…
FIGURE 5
The diverse features of GC…
FIGURE 5
The diverse features of GC classified by signature score. The immunotherapy‐related features (MSI/EBV…
FIGURE 6
EV‐derived PD‐L1 and PD‐L2 exerted…
FIGURE 6
EV‐derived PD‐L1 and PD‐L2 exerted opposite impacts on the tumour growth inhibition of…
FIGURE 7
Immunotherapy combined with HER2‐targeted therapy…
FIGURE 7
Immunotherapy combined with HER2‐targeted therapy was a potential option for GC patients with…
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- Chalfin, H. J. , Pramparo, T. , Mortazavi, A. , Niglio, S. A. , Schonhoft, J. D. , Jendrisak, A. , Chu, Y.‐L. , Richardson, R. , Krupa, R. , Anderson, A. K. L. , Wang, Y. , Dittamore, R. , Pal, S. K. , Lara, P. N. , Stein, M. N. , Quinn, D. I. , Steinberg, S. M. , Cordes, L. M. , Ley, L. , & Apolo, A. B. (2021). Circulating tumor cell subtypes and T‐cell populations as prognostic biomarkers to combination immunotherapy in patients with metastatic genitourinary cancer. Clinical Cancer Research, 27(5), 1391–1398. - PMC - PubMed
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- Chen, G. , Huang, A. C. , Zhang, W. , Zhang, G. , Wu, M. , Xu, W. , Yu, Z. , Yang, J. , Wang, B. , Sun, H. , Xia, H. , Man, Q. , Zhong, W. , Antelo, L. F. , Wu, B. , Xiong, X. , Liu, X. , Guan, L. , Li, T. , & Guo, W. (2018). Exosomal PD‐L1 contributes to immunosuppression and is associated with anti‐PD‐1 response. Nature, 560(7718), 382–386. - PMC - PubMed
- Research Support, Non-U.S. Gov't
- Extracellular Vesicles*
- Humans
- Immunotherapy
- Retrospective Studies
- Stomach Neoplasms* / therapy
- 81872341/National Natural Science Foundation of China
- 81802327/National Natural Science Foundation of China
- 2019-1/The third round of public welfare development and reform pilot projects of Beijing Municipal Medical Research Institutes, Beijing Medical Research Institute
- Y-2019AZQN-0070/Xisike-leader Oncology Research Foundation
- QML20201102/Beijing Hospitals Authority Youth Programme
- Full Text Sources
- Medical
- Research Materials
- Miscellaneous
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Source: PubMed