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
FIGURE 1
The expressional landscape of plasma EV protein panel in GC treated with ICI‐related therapy. (a) An overall work flow of the whole study. (b) A sketch map for the procedures of EV expression array. (c) The overall response and prognostic features of the training cohort. (d) The hierarchical‐clustered heatmap of EV protein panel for all time points in the training cohort. (e) Comparison of EV‐derived PD‐L1 expression between patients defined as tissue CPS‐negative and ‐positive. Correlations between EV‐derived CD3 expression and circulating T cell number, or between EV‐derived CD19 expression and circulating B cell number in paired peripheral blood samples (f) at BL or (g) for all time points were assessed. CPSpos, CPS positive. CPSneg, CPS negative
FIGURE 2
FIGURE 2
A four protein‐based plasma EV‐score at treatment baseline robustly predicted immunotherapeutic outcomes. The prognostic correlations of EV‐derived (a) ARG1, (b) CD3, (c) PD‐L1 and (d) PD‐L2 at BL were assessed by Kaplan‐Meier survival analysis. These four genes were further combined to generated an EV‐score. (e) ROC curve was used to measure the specificity and sensitivity of EV‐derived ARG1, CD3, PD‐L1, PD‐L2 and EV‐score in characterizing patients reached an irPFS (progression) or irOS (survival) longer than 6 months. (f) Prognostic indications of scattered EV‐scores (left panel), or for the cut‐off value of EV‐score≥1 (right panel). (g) Timeline‐scaled changes of tumour volume and (h) the best changes of tumour volume for all patients were stratified by EV‐score. CT images and changes of tumour volume were displayed for representative cases defined as (i) EV‐score≥1 or (j) EV‐score 

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 3
EV‐score dynamically monitored ICI outcomes. (a) Fold changes of EV protein panel and score at 1 M compared with BL in 18 accessible patients. (b) The prognostic correlations of EV‐derived ARG1, CD3, PD‐L1, PD‐L2 and (c) EV‐score at 1 M were assessed by Kaplan‐Meier survival analysis. (d) Correlation between EV‐score and IFN‐γ level in paired peripheral blood samples for all time points. (e) Expressions of EV‐derived ARG1, CD3, PD‐L1, PD‐L2 and (f) value of EV‐score were compared at BL, CR/PR, SD, PD points. (g) Dynamic changes of EV‐score along with the timeline of ICI treatment were compared between patients with/without overall response, disease control, disease progression and cancer death. Dynamic changes of (h) EV‐score, (i) cytotoxic cytokines IFN‐γ/TNF‐α, (j) T cell (CD3+CD8+)/activated T cell (CD8+CD28+)/NK cell (CD3–CD16+56+) and (k) tumour markers CEA/CA199/CA125 along with the timeline of ICI treatment were compared between patients defined as BL EV‐score≥1 or BL EV‐score < 1. *, P < 0.05. ns, P value not significant

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 4
EV‐score predicted ICI outcomes for a prospective validating cohort. (a) The prognostic correlations of EV‐score at BL were assessed in a prospective validating cohort. (b) ROC curve‐measured specificity and sensitivity of EV‐score in characterizing patients reached a PFS longer than 6 months. (c) Prognostic role of EV‐score for patients received 1st line treatment and (d) patients received > 1st line treatment, as well as (e) CPS‐positive and (f) CPS‐negative patients. (g) Timeline‐scaled changes of tumour volume and (h) the best changes of tumour volume for all patients were stratified by EV‐score. CT images and changes of tumour volume were displayed for representative cases defined as (i) EV‐score≥1 or (j) EV‐score < 1. Dynamic changes of (k) T cell (CD3+CD8+)/activated T cell (CD8+CD28+)/NK cell (CD3–CD16+56+) and (l) tumour markers CEA/CA199/CA125 along with the timeline of ICI treatment were compared between patients defined as BL EV‐score≥1 or BL EV‐score < 1. CPSpos, CPS positive. CPSneg, CPS negative

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 5
The diverse features of GC classified by signature score. The immunotherapy‐related features (MSI/EBV status) and tissue HER2 positivity were classified by EV‐score in (a) training and (b) validating cohorts. The mutual correlations among tissue‐based transcriptomic ARG1, CD3, PD‐L1, PD‐L2 expressions and tissue‐score were assessed in (c) TCGA and (d) GSE62254 datasets. The immunotherapy‐related features (MSI/EBV status) and ERBB2 amplification were classified by tissue‐score in (e) TCGA and (f) GSE62254 datasets. The tissue‐based TH1/TH2 ratio, activated T cell and NK cell were classified by tissue‐score in (g) TCGA and (h) GSE62254 datasets. The tissue‐based transcriptomic IFN‐γ, perforin and granzyme A/B/H/K/M expressions were classified by tissue‐score in (i) TCGA and (j) GSE62254 datasets

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 6
EV‐derived PD‐L1 and PD‐L2 exerted opposite impacts on the tumour growth inhibition of anti‐PD‐1 agent. (a) The expression of PD‐L1 or PD‐L2 in mouse cancer cell lines MC38/CT26. (b) Western Blot assay for EV markers of isolated cellular EV samples. (c) ELISA quantification for the concentration of PD‐L1 or PD‐L2 expression in 5 μg extracted EVs. The time‐scaled changes of (d) mice body weight, (e) tumour volume and (f) images of xenograft tumours on the last day of treatment were recorded for MC38/CT26 xenografts. (g) The staining of HE, ki‐67 and CD8 in MC38/CT26 xenograft tumours were displayed. The (h) TH1/TH2 ratio and the expression of (i) IFN‐γ, (j) TNF‐α, (k) granzyme B in CT26 xenograft tumours were quantified. *, P < 0.05. ns, P value not significant

FIGURE 7

Immunotherapy combined with HER2‐targeted therapy…

FIGURE 7

Immunotherapy combined with HER2‐targeted therapy was a potential option for GC patients with…

FIGURE 7
Immunotherapy combined with HER2‐targeted therapy was a potential option for GC patients with low EV‐score. (a) The distribution of four biomarker EV proteins, EV‐score and tissue HER2 positivity for ICI+H (expanding) cohort. (b) The overall response and prognostic features of the expanding cohort. The prognostic correlations of EV‐score at BL were assessed for (c) the tissue HER2 positive patients in combining the training and validating cohort, or for (d) all patients in the expanding cohort. CT images and changes of tumour volume for representative cases defined as (e) EV‐score≥1 or (f) EV‐score 
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References
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FIGURE 3
FIGURE 3
EV‐score dynamically monitored ICI outcomes. (a) Fold changes of EV protein panel and score at 1 M compared with BL in 18 accessible patients. (b) The prognostic correlations of EV‐derived ARG1, CD3, PD‐L1, PD‐L2 and (c) EV‐score at 1 M were assessed by Kaplan‐Meier survival analysis. (d) Correlation between EV‐score and IFN‐γ level in paired peripheral blood samples for all time points. (e) Expressions of EV‐derived ARG1, CD3, PD‐L1, PD‐L2 and (f) value of EV‐score were compared at BL, CR/PR, SD, PD points. (g) Dynamic changes of EV‐score along with the timeline of ICI treatment were compared between patients with/without overall response, disease control, disease progression and cancer death. Dynamic changes of (h) EV‐score, (i) cytotoxic cytokines IFN‐γ/TNF‐α, (j) T cell (CD3+CD8+)/activated T cell (CD8+CD28+)/NK cell (CD3–CD16+56+) and (k) tumour markers CEA/CA199/CA125 along with the timeline of ICI treatment were compared between patients defined as BL EV‐score≥1 or BL EV‐score < 1. *, P < 0.05. ns, P value not significant
FIGURE 4
FIGURE 4
EV‐score predicted ICI outcomes for a prospective validating cohort. (a) The prognostic correlations of EV‐score at BL were assessed in a prospective validating cohort. (b) ROC curve‐measured specificity and sensitivity of EV‐score in characterizing patients reached a PFS longer than 6 months. (c) Prognostic role of EV‐score for patients received 1st line treatment and (d) patients received > 1st line treatment, as well as (e) CPS‐positive and (f) CPS‐negative patients. (g) Timeline‐scaled changes of tumour volume and (h) the best changes of tumour volume for all patients were stratified by EV‐score. CT images and changes of tumour volume were displayed for representative cases defined as (i) EV‐score≥1 or (j) EV‐score < 1. Dynamic changes of (k) T cell (CD3+CD8+)/activated T cell (CD8+CD28+)/NK cell (CD3–CD16+56+) and (l) tumour markers CEA/CA199/CA125 along with the timeline of ICI treatment were compared between patients defined as BL EV‐score≥1 or BL EV‐score < 1. CPSpos, CPS positive. CPSneg, CPS negative
FIGURE 5
FIGURE 5
The diverse features of GC classified by signature score. The immunotherapy‐related features (MSI/EBV status) and tissue HER2 positivity were classified by EV‐score in (a) training and (b) validating cohorts. The mutual correlations among tissue‐based transcriptomic ARG1, CD3, PD‐L1, PD‐L2 expressions and tissue‐score were assessed in (c) TCGA and (d) GSE62254 datasets. The immunotherapy‐related features (MSI/EBV status) and ERBB2 amplification were classified by tissue‐score in (e) TCGA and (f) GSE62254 datasets. The tissue‐based TH1/TH2 ratio, activated T cell and NK cell were classified by tissue‐score in (g) TCGA and (h) GSE62254 datasets. The tissue‐based transcriptomic IFN‐γ, perforin and granzyme A/B/H/K/M expressions were classified by tissue‐score in (i) TCGA and (j) GSE62254 datasets
FIGURE 6
FIGURE 6
EV‐derived PD‐L1 and PD‐L2 exerted opposite impacts on the tumour growth inhibition of anti‐PD‐1 agent. (a) The expression of PD‐L1 or PD‐L2 in mouse cancer cell lines MC38/CT26. (b) Western Blot assay for EV markers of isolated cellular EV samples. (c) ELISA quantification for the concentration of PD‐L1 or PD‐L2 expression in 5 μg extracted EVs. The time‐scaled changes of (d) mice body weight, (e) tumour volume and (f) images of xenograft tumours on the last day of treatment were recorded for MC38/CT26 xenografts. (g) The staining of HE, ki‐67 and CD8 in MC38/CT26 xenograft tumours were displayed. The (h) TH1/TH2 ratio and the expression of (i) IFN‐γ, (j) TNF‐α, (k) granzyme B in CT26 xenograft tumours were quantified. *, P < 0.05. ns, P value not significant
FIGURE 7
FIGURE 7
Immunotherapy combined with HER2‐targeted therapy was a potential option for GC patients with low EV‐score. (a) The distribution of four biomarker EV proteins, EV‐score and tissue HER2 positivity for ICI+H (expanding) cohort. (b) The overall response and prognostic features of the expanding cohort. The prognostic correlations of EV‐score at BL were assessed for (c) the tissue HER2 positive patients in combining the training and validating cohort, or for (d) all patients in the expanding cohort. CT images and changes of tumour volume for representative cases defined as (e) EV‐score≥1 or (f) EV‐score 
All figures (7)

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