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iNature's immune checkpoint inhibitor (ICI)-based immunotherapy brings new hope for gastric cancer (GC) treatment
.
However, patient selection and outcome prediction for GC immunotherapy remain unsatisfactory due to the lack of appropriate biomarkers
.
On March 31, 2022, Shen Lin, Zhang Xiaotian of Peking University, and Gao Jing of Chinese Academy of Medical Sciences/Peking Union Medical College jointly published an online journal of Extracellular Vesicles (IF=26) entitled "Plasma extracellular vesicle derived protein profile predicting and monitoring immunotherapeutic outcomes of gastric cancer", which assessed the correlation of plasma EV-derived protein profiles with outcomes of ICI-related treatment combinations by applying extracellular vesicle (EV) protein expression arrays
.
The plasma of 112 GC patients receiving ICI-related therapy was retrospectively/prospectively studied as three cohorts
.
The study identified four plasma EV-derived proteins (ARG1/CD3/PD-L1/PD-L2) from 42 key candidate proteins and combined them into an EV score that reliably predicts immunotherapy outcome at baseline and Dynamic monitoring of disease progression and treatment
.
High EV-score reflects microenvironmental features with stronger anti-tumor immunity, manifested by more activation of CD8+ T/NK cells, higher TH1/TH2 ratio, and expression of IFN-γ/perforin/granzyme in paired peripheral blood Higher, validated by dataset analysis and in vivo experiments
.
GC with EV-score ≥ 1 obtained more therapeutic benefit from ICI, while GC with EV-score < 1 may benefit more from ICI combined with HER2-targeted therapy
.
Overall, by proposing a protein-level plasma EV score that can effectively predict and monitor immunotherapy outcomes in GC, this research work facilitates clinical patient selection and decision-making and provides insights into immunotherapy-related microenvironmental changes and current ICIs.
Improvements to the protocol provide mechanistic insights
.
Gastric cancer (GC) is the fifth most common cancer type worldwide and the third leading cause of cancer death
.
Due to its high heterogeneity and complex tissue composition, advanced GC derives limited therapeutic benefit from standard therapy, necessitating additional precision medicine options
.
The development of molecular subtypes has provided more precise treatment options for GC, especially immunotherapy
.
Immune checkpoint inhibitors (ICIs) can rescue the patient's immune system and undo/enhance adaptive immunity against cancer, resulting in consistent antitumor efficacy in heterogeneous patients
.
Inspired by the success of a series of clinical trials, ICIs have been successfully approved as first-line and adjuvant therapy for gastroesophageal cancer
.
However, although ICI provides patients with significant clinical outcomes, the response rate of unselected GCs to anti-PD-1/anti-PD-L1 immunotherapy is only around 20%
.
Patients with certain genomic and molecular features, including microsatellite instability (MSI)/EBV positivity/high tumor mutational burden (TMB)/high PD-L1 expression (as represented by CPS, composite positivity score), are expected to more benefit from immunotherapy, but these patients represent only a small fraction of the GC population
.
Furthermore, these features are imperfect predictors of ICI outcomes, and acquired resistance can compromise treatment efficacy
.
Therefore, to improve the management and clinical decision-making of ICI in GC, there is an urgent need to develop new methods to facilitate patient selection and to assess disease progression in time as treatment progresses
.
Schematic diagram of the procedure for EV expression arrays (image from Journal of Extracellular Vesicles).
Extracellular vesicles (EVs) are membrane-bound nano-sized particles detected in nearly all types of body fluids, including plasma
.
With systemic or local blood/lymph circulation, EVs transfer multiple biologically active cargoes, including DNA/RNA/protein, to direct cell-cell or cell-microenvironment communication and mediate multiple cancer events, including malignant transformation/angiogenesis /metastasis/drug resistance/immune evasion
.
Due to their cancer-related roles, EVs are a rising star in liquid biopsy and have been used in clinical applications such as early detection of cancer
.
However, the relationship between EV content and immunotherapy outcome in GC has not been systematically addressed
.
On the other hand, since proteins are direct performers of biological activities, immunotherapy-induced changes in the tumor microenvironment can be recorded and presented by EV-derived proteins
.
Current studies have mainly investigated the role of EVs in liquid biopsies from the perspective of noncoding RNAs, but little has been reported on the effects of EV-derived protein components
.
In this study, 199 plasma samples from 112 GC patients undergoing an ICI-related regimen were recruited into three independent cohorts for a combined analysis
.
By applying plasma-based protein expression arrays, this study profiled 42 key EV-derived proteins and screened 4 members from them to generate EV scores to reliably predict/monitor the outcome of GC immunotherapy
.
The study also analyzes the microenvironmental features, phenotypes, and mechanisms that characterize this plasma EV score, and discusses the possibility of ICI plus HER2-targeted therapy as an alternative for patients who do not benefit from ICI
.
Overall, this work provides a novel GC immunotherapy biomarker in view of plasma EV-derived proteins
.
Reference message: https://onlinelibrary.
wiley.
com/doi/10.
1002/jev2.
12209
.
However, patient selection and outcome prediction for GC immunotherapy remain unsatisfactory due to the lack of appropriate biomarkers
.
On March 31, 2022, Shen Lin, Zhang Xiaotian of Peking University, and Gao Jing of Chinese Academy of Medical Sciences/Peking Union Medical College jointly published an online journal of Extracellular Vesicles (IF=26) entitled "Plasma extracellular vesicle derived protein profile predicting and monitoring immunotherapeutic outcomes of gastric cancer", which assessed the correlation of plasma EV-derived protein profiles with outcomes of ICI-related treatment combinations by applying extracellular vesicle (EV) protein expression arrays
.
The plasma of 112 GC patients receiving ICI-related therapy was retrospectively/prospectively studied as three cohorts
.
The study identified four plasma EV-derived proteins (ARG1/CD3/PD-L1/PD-L2) from 42 key candidate proteins and combined them into an EV score that reliably predicts immunotherapy outcome at baseline and Dynamic monitoring of disease progression and treatment
.
High EV-score reflects microenvironmental features with stronger anti-tumor immunity, manifested by more activation of CD8+ T/NK cells, higher TH1/TH2 ratio, and expression of IFN-γ/perforin/granzyme in paired peripheral blood Higher, validated by dataset analysis and in vivo experiments
.
GC with EV-score ≥ 1 obtained more therapeutic benefit from ICI, while GC with EV-score < 1 may benefit more from ICI combined with HER2-targeted therapy
.
Overall, by proposing a protein-level plasma EV score that can effectively predict and monitor immunotherapy outcomes in GC, this research work facilitates clinical patient selection and decision-making and provides insights into immunotherapy-related microenvironmental changes and current ICIs.
Improvements to the protocol provide mechanistic insights
.
Gastric cancer (GC) is the fifth most common cancer type worldwide and the third leading cause of cancer death
.
Due to its high heterogeneity and complex tissue composition, advanced GC derives limited therapeutic benefit from standard therapy, necessitating additional precision medicine options
.
The development of molecular subtypes has provided more precise treatment options for GC, especially immunotherapy
.
Immune checkpoint inhibitors (ICIs) can rescue the patient's immune system and undo/enhance adaptive immunity against cancer, resulting in consistent antitumor efficacy in heterogeneous patients
.
Inspired by the success of a series of clinical trials, ICIs have been successfully approved as first-line and adjuvant therapy for gastroesophageal cancer
.
However, although ICI provides patients with significant clinical outcomes, the response rate of unselected GCs to anti-PD-1/anti-PD-L1 immunotherapy is only around 20%
.
Patients with certain genomic and molecular features, including microsatellite instability (MSI)/EBV positivity/high tumor mutational burden (TMB)/high PD-L1 expression (as represented by CPS, composite positivity score), are expected to more benefit from immunotherapy, but these patients represent only a small fraction of the GC population
.
Furthermore, these features are imperfect predictors of ICI outcomes, and acquired resistance can compromise treatment efficacy
.
Therefore, to improve the management and clinical decision-making of ICI in GC, there is an urgent need to develop new methods to facilitate patient selection and to assess disease progression in time as treatment progresses
.
Schematic diagram of the procedure for EV expression arrays (image from Journal of Extracellular Vesicles).
Extracellular vesicles (EVs) are membrane-bound nano-sized particles detected in nearly all types of body fluids, including plasma
.
With systemic or local blood/lymph circulation, EVs transfer multiple biologically active cargoes, including DNA/RNA/protein, to direct cell-cell or cell-microenvironment communication and mediate multiple cancer events, including malignant transformation/angiogenesis /metastasis/drug resistance/immune evasion
.
Due to their cancer-related roles, EVs are a rising star in liquid biopsy and have been used in clinical applications such as early detection of cancer
.
However, the relationship between EV content and immunotherapy outcome in GC has not been systematically addressed
.
On the other hand, since proteins are direct performers of biological activities, immunotherapy-induced changes in the tumor microenvironment can be recorded and presented by EV-derived proteins
.
Current studies have mainly investigated the role of EVs in liquid biopsies from the perspective of noncoding RNAs, but little has been reported on the effects of EV-derived protein components
.
In this study, 199 plasma samples from 112 GC patients undergoing an ICI-related regimen were recruited into three independent cohorts for a combined analysis
.
By applying plasma-based protein expression arrays, this study profiled 42 key EV-derived proteins and screened 4 members from them to generate EV scores to reliably predict/monitor the outcome of GC immunotherapy
.
The study also analyzes the microenvironmental features, phenotypes, and mechanisms that characterize this plasma EV score, and discusses the possibility of ICI plus HER2-targeted therapy as an alternative for patients who do not benefit from ICI
.
Overall, this work provides a novel GC immunotherapy biomarker in view of plasma EV-derived proteins
.
Reference message: https://onlinelibrary.
wiley.
com/doi/10.
1002/jev2.
12209
