Abstract
ObjectivesEpstein–Barr virus (EBV) infection is associated with a better response to anti‐PD1 immunotherapy. We hypothesised that genetic alterations induced by EBV infection are responsible for the activation of key immune responses and hence are predictive of anti‐PD1 efficacy.MethodsWith transcriptome data of gastric cancer (GC), we explored differentially expressed genes (DEGs) specific for EBV infection and performed coexpression network analysis using the DEGs to identify the consistent coexpression genes (CCGs) between EBV‐positive and EBV‐negative GC tissues. We selected the tag genes of the CCGs and validated them using RNA sequencing and immunohistochemistry. We established murine models and collected tissues from clinical patients to test the value of SLAMF8 in predicting anti‐PD1 treatment. The location and expression of SLAMF8 were characterised by multiplex immunofluorescence and quantitative PCR. Moreover, exogenous overexpression and RNA‐sequencing analysis were used to test the potential function of SLAMF8.ResultsWe identified 290 CCGs and validated the tag gene SLAMF8 in transcriptome data of gastrointestinal cancer (GI). We observed that the T‐cell activation pathway was significantly enriched in high‐expression SLAMF8 GI cancers. Higher SLAMF8 expression was positively associated with CD8 expression and a better response to anti‐PD1 treatment. We further observed dynamically increased expression of SLAMF8 in murine models relatively sensitive to anti‐PD1 treatment. SLAMF8 was mainly expressed on the surface of macrophages. Exogenous overexpression of SLAMF8 in macrophages resulted in enrichment of positive regulation of multiple immune‐related pathways.ConclusionHigher SLAMF8 expression may predict better anti‐PD1 immunotherapy efficacy in GI cancer.
Highlights
Gastrointestinal (GI) cancer has a high incidence and mortality rate and remains a major public health problem worldwide,[1] and the 5-year survival of advanced GI cancer patients remains as poor as 10%.2,3 Recently, several immune checkpoint inhibitors, anti-PD1 monoclonal antibodies, have been approved for the first-line treatment of several cancers by the US Food and Drug Administration
1846 and 3190 genes were identified to be differentially expressed in Epstein–Barr virus (EBV)+ and EBVÀ gastric cancer (GC) tissues compared with corresponding adjacent normal tissues
The expression of these 7 checkpoint genes was upregulated in EBV+ GC tissues compared with adjacent normal tissues (Supplementary figure 1a) and obviously increased in EBV+ GC compared with EBVÀ GC, indicating the potential involvement of the signature in driving the immune checkpoint
Summary
Gastrointestinal (GI) cancer has a high incidence and mortality rate and remains a major public health problem worldwide,[1] and the 5-year survival of advanced GI cancer patients remains as poor as 10%.2,3 Recently, several immune checkpoint inhibitors, anti-PD1 monoclonal antibodies (mAbs), have been approved for the first-line treatment of several cancers by the US Food and Drug Administration. Recent studies have suggested that PDL1 expression, tumor mutation burden and microsatellite instability status of tumor tissues are potential predictors of the efficacy of anti-PD1 therapy.[6,7,8,9] The implementation of biomarkerguided personalised anti-PD1 therapy has improved the efficacy in patients with advanced solid tumors, with an increased overall response rate of 34.1% for patients with high-expression PD-L110 and 53% (42–64%) for those with microsatellite instabilityhigh tumors.[11] Because of these novel findings, US Food and Drug Administration and National Comprehensive Cancer Network guidelines have recommended pembrolizumab, an anti-PD1 agent, for the treatment of patients with microsatellite instability-high or DNA mismatch repair deficiency, regardless of the site of primary tumors. This considerable achievement has led to attempts to find more novel biomarkers to guide anti-PD1 immunotherapy in a personalised way, which is the focus in a series of recent studies.[12,13,14,15]
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