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The evolving immunotherapeutic landscape in advanced oesophagogastric cancer.

ABSTRACT: Improvements in median overall survival in the advanced oesophagogastric (OG) setting have plateaued, underlining the need for improved therapeutic approaches in this patient population. Immunotherapeutics are inducing unexpected durable responses in an expanding list of advanced disease indications. Although OG cancers have traditionally been considered to be more challenging to treat with immunotherapy than some other malignancies because of their variable tumour mutational burden and relative scarcity of infiltrating T cells, immune checkpoint inhibitor (ICPI) trials conducted over the last few years suggest there is an important role for these treatments. ICPI efficacy may be demonstrated in specific molecular subtypes of OG cancer. This review outlines the improvements in defining predictive biomarkers of responsiveness to ICPIs. Increasingly, identification of an expanding list of ICPI resistance mechanisms will drive biomarker-directed research. In addition, the specific rationale to combine ICPIs with chemotherapies, radiotherapies, targeted therapies and other novel immunotherapeutic drugs will be discussed.

SUBMITTER: Flynn M

PROVIDER: S-EPMC6048671 | biostudies-literature | 2018

REPOSITORIES: biostudies-literature

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The evolving immunotherapeutic landscape in advanced oesophagogastric cancer.

Flynn Michael M Young Kate K Cunningham David D Starling Naureen N

Therapeutic advances in medical oncology 20180711

Improvements in median overall survival in the advanced oesophagogastric (OG) setting have plateaued, underlining the need for improved therapeutic approaches in this patient population. Immunotherapeutics are inducing unexpected durable responses in an expanding list of advanced disease indications. Although OG cancers have traditionally been considered to be more challenging to treat with immunotherapy than some other malignancies because of their variable tumour mutational burden and relative ...[more]

PMID: 30034550

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Project description:BackgroundAdvanced gastric cancer (AGC) is a disease with poor prognosis due to the current lack of effective therapeutic strategies. Immune checkpoint blockade treatments have shown effective responses in patient subgroups but biomarkers remain challenging. Traditional classification of gastric cancer (GC) is based on genomic profiling and molecular features. Therefore, it is critical to identify the immune-related subtypes and predictive markers by immuno-genomic profiling.MethodsSingle-sample gene-set enrichment analysis (ssGSEA) and ESTIMATE algorithm were used to identify the immue-related subtypes of AGC in two independent GEO datasets. Weighted gene co-expression network analysis (WGCNA) and Molecular Complex Detection (MCODE) algorithm were applied to identify hub-network of immune-related subtypes. Hub genes were confirmed by prognostic data of KMplotter and GEO datasets. The value of hub-gene in predicting immunotherapeutic response was analyzed by IMvigor210 datasets. MTT assay, Transwell migration assay and Western blotting were performed to confirm the cellular function of hub gene in vitro.ResultsThree immune-related subtypes (Immunity_H, Immunity_M and Immunity_L) of AGC were identified in two independent GEO datasets. Compared to Immunity_L, the Immuntiy_H subtype showed higher immune cell infiltration and immune activities with favorable prognosis. A weighted gene co-expression network was constructed based on GSE62254 dataset and identified one gene module which was significantly correlated with the Immunity_H subtype. A Hub-network which represented high immune activities was extracted based on topological features and Molecular Complex Detection (MCODE) algorithm. Furthermore, ADAM like decysin 1 (ADAMDEC1) was identified as a seed gene among hub-network genes which is highly associated with favorable prognosis in both GSE62254 and external validation datasets. In addition, high expression of ADAMDEC1 correlated with immunotherapeutic response in IMvigor210 datasets. In vitro, ADAMDEC1 was confirmed as a potential protein in regulating proliferation and migration of gastric cancer cell. Deficiency of ADAMDEC1 of gastric cancer cell also associated with high expression of PD-L1 and Jurkat T cell apoptosis.ConclusionsWe identified immune-related subtypes and key tumor microenvironment marker in AGC which might facilitate the development of novel immune therapeutic targets.

Dataset Information

The evolving immunotherapeutic landscape in advanced oesophagogastric cancer.

Publications

The evolving immunotherapeutic landscape in advanced oesophagogastric cancer.

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