Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment

Chen, Yang; Jia, Keren; Sun, Yu; Zhang, Cheng; Li, Yilin; Zhang, Li; Chen, Zifan; Zhang, Jiangdong; Hu, Yonggang; Yuan, Jiajia; Zhao, Xingwang; Li, Yanyan; Gong, Jifang; Dong, Bin; Zhang, Xiaotian; Li, Jian; Shen, Lin

doi:10.1038/s41467-022-32570-z

Cited by 80 publications

(70 citation statements)

References 39 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Immune checkpoint inhibitors (ICIs) bring new hope to tumor patients due to their significant efficacy and low side effects. However, the response rate of immunotherapy for patients with advanced gastric cancer is less than 30% (Chen et al, 2022), which limits their use in clinical treatment. Studies have shown that the tumor microenvironment (TME) plays a vital role in tumor development and can influence the response rate of ICIs .…”

Section: Introductionmentioning

confidence: 99%

Identification of TGF-β signaling-related molecular patterns, construction of a prognostic model, and prediction of immunotherapy response in gastric cancer

Zeng

Dai

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

Background: TGF-β signaling pathway plays an essential role in tumor progression and immune responses. However, the link between TGF-β signaling pathway-related genes (TSRGs) and clinical prognosis, tumor microenvironment (TME), and immunotherapy in gastric cancer is unclear.Methods: Transcriptome data and related clinical data of gastric cancer were downloaded from the Cancer Genome Atlas (TCGA) and Gene Expression Omnibus (GEO) databases, and 54 TSRGs were obtained from the Molecular Signatures Database (MSigDB). We systematically analyzed the expression profile characteristics of 54 TSRGs in 804 gastric cancer samples and examined the differences in prognosis, clinicopathological features, and TME among different molecular subtypes. Subsequently, TGF-β-related prognostic models were constructed using univariate and least absolute shrinkage and selection operator (LASSO) Cox regression analysis to quantify the degree of risk in each patient. Patients were divided into two high- and low-risk groups based on the median risk score. Finally, sensitivity to immune checkpoint inhibitors (ICIs) and anti-tumor agents was assessed in patients in high- and low-risk groups.Results: We identified two distinct TGF-β subgroups. Compared to TGF-β cluster B, TGF-β cluster A exhibits an immunosuppressive microenvironment with a shorter overall survival (OS). Then, a novel TGF-β-associated prognostic model, including SRPX2, SGCE, DES, MMP7, and KRT17, was constructed, and the risk score was demonstrated as an independent prognostic factor for gastric cancer patients. Further studies showed that gastric cancer patients in the low-risk group, characterized by higher tumor mutation burden (TMB), the proportion of high microsatellite instability (MSI-H), immunophenoscore (IPS), and lower tumor immune dysfunction and exclusion (TIDE) score, had a better prognosis, and linked to higher response rate to immunotherapy. In addition, the risk score and anti-tumor drug sensitivity were strongly correlated.Conclusion: These findings highlight the importance of TSRGs, deepen the understanding of tumor immune microenvironment, and guide individualized immunotherapy for gastric cancer patients.

show abstract

Section: Introductionmentioning

confidence: 99%

Identification of TGF-β signaling-related molecular patterns, construction of a prognostic model, and prediction of immunotherapy response in gastric cancer

Zeng

Dai

et al. 2022

Front. Pharmacol.

View full text Add to dashboard Cite

show abstract

“…The response to cancer therapy dramatically varies among cancer patients (10)(11)(12). Intrinsic reasons behind heterogeneous clinical responses have not yet been illuminated.…”

mentioning

confidence: 99%

The crosstalk between the gut microbiota and tumor immunity: Implications for cancer progression and treatment outcomes

et al. 2023

View full text Add to dashboard Cite

The gastrointestinal tract is inhabited by trillions of commensal microorganisms that constitute the gut microbiota. As a main metabolic organ, the gut microbiota has co-evolved in a symbiotic relationship with its host, contributing to physiological homeostasis. Recent advances have provided mechanistic insights into the dual role of the gut microbiota in cancer pathogenesis. Particularly, compelling evidence indicates that the gut microbiota exerts regulatory effects on the host immune system to fight against cancer development. Some microbiota-derived metabolites have been suggested as potential activators of antitumor immunity. On the contrary, the disequilibrium of intestinal microbial communities, a condition termed dysbiosis, can induce cancer development. The altered gut microbiota reprograms the hostile tumor microenvironment (TME), thus allowing cancer cells to avoid immunosurvelliance. Furthermore, the gut microbiota has been associated with the effects and complications of cancer therapy given its prominent immunoregulatory properties. Therapeutic measures that aim to manipulate the interplay between the gut microbiota and tumor immunity may bring new breakthroughs in cancer treatment. Herein, we provide a comprehensive update on the evidence for the implication of the gut microbiota in immune-oncology and discuss the fundamental mechanisms underlying the influence of intestinal microbial communities on systemic cancer therapy, in order to provide important clues toward improving treatment outcomes in cancer patients.

show abstract

“…In addition, macrophages could secrete CXCL8 and contribute to the immunosuppressive microenvironment by inducing PD-L1 + subtype [71]. In Chen et al study, a CD68 + STING + macrophage subtype was identified to result in inferior OS with higher density, suggesting that STING or macrophages are negative prognosticators of GC [72]. Interestingly, the CD68 + STING + macrophage was also associated with a negative response to anti-PD-1/PD-L1 therapy.…”

Section: Discussionmentioning

confidence: 99%

Bleomycin alters intratumoral immune response of EBV-associated gastric cancer by ENTPD8 and PCOLCE2

Chen

2023

Preprint

View full text Add to dashboard Cite

Background EBV-associated gastric cancer (EBVaGC) with high PD-L1 level, is most likely to be the next subgroup benefited from immunotherapy. However, complicated with histological and aetiological heterogeneity, tolerance persists which was usually alleviated by clinical adjuvant chemotherapy (bleomycin). Identifying biomarkers of intratumoral immune response was critical for further understanding the direct mechanism of immunotherapy effectiveness. Method Firstly, to identify gene sets involved in both GC tumorigenesis and EBV infection, a transcriptome sequencing data (GSE51575) was collected for different expression gene (DEG) screening and functional enrichment analysis. Through constructing a prognostic model based on 25 repeated DEGs and evaluating immune correlations subsequently, the influence of ENTPD8 and PCOLCE2 in prognosis and immunotherapy was confirmed. In addition, the binding energy between bleomycin and targets was calculated based on hydrogen bond. Result A total of 572 down- and 162 up-regulated genes in normal tissue vs. GC tissue while 196 down- and 240 up-regulated genes in EBVnGC vs. EBVaGC were detected with logFC ≥ 2 and p-value ≤ 0.05. Among them, ENTPD8 and PCOLCE2 were reduced in EBVaGC which was associated with prognosis significantly and mediated dysregulation of immune response inversely. Besides, the expression trends of ENTPD8 (positive) and PCOLCE2 (negative) were also opposite when binding to bleomycin with the most stable binding energy-4.589 kcal/mol and − 4.025 kcal/mol, respectively. Conclusion Summarily, the improvement of immunotherapy caused by bleomycin as an adjuvant chemotherapy drug may mainly depend on the fluctuation of intratumoral immune response in EBVaGC mediated by the expression of ENTPD8 and PCOLCE2.

show abstract

Predicting response to immunotherapy in gastric cancer via multi-dimensional analyses of the tumour immune microenvironment

Cited by 80 publications

References 39 publications

Identification of TGF-β signaling-related molecular patterns, construction of a prognostic model, and prediction of immunotherapy response in gastric cancer

Identification of TGF-β signaling-related molecular patterns, construction of a prognostic model, and prediction of immunotherapy response in gastric cancer

The crosstalk between the gut microbiota and tumor immunity: Implications for cancer progression and treatment outcomes

Bleomycin alters intratumoral immune response of EBV-associated gastric cancer by ENTPD8 and PCOLCE2

Contact Info

Product

Resources

About