Abstract
Gastric cancer (GC) is a complex and heterogeneous disease, making it difficult to ascertain the optimal therapeutic approach for individual GC patients. Stromal and immune cell infiltration in GC has a strong correlation with clinical outcomes; however, the underlying mechanisms that drive immunosuppression remain vastly undiscovered. Recent studies validated that anthrax toxin receptor 1 (ANTXR1) is aberrantly expressed in several cancers and holds promise as a new therapeutic target for cancer. However, its immunological roles in GC are still unclear. Here, we show that we identify the distinct stromal and immune cell infiltration in GC between the high and low ANTXR1 expression group by analyzing genomic data. Clinically, ANTXR1 is highly expressed in GC and correlates with adverse clinicopathological characteristics. Additionally, high ANTXR1 expression is linked to markedly poor clinical outcomes and resistance to chemotherapy, whereas the low ANTXR1 expression group is correlated with better outcomes and response to chemotherapy in GC patients. We further revealed the differential landscape of somatic tumor mutation burden (TMB) between the two groups and observed that patients with high ANTXR1 expression suffered from a lower TMB, potentially leading to less sensitivity to checkpoint therapy. Molecularly, results displayed that ANTXR1 is an immunosuppressive element, which may perform its function via promoting the secretion of immunosuppressive factors that play a significant role in modulating tumor-associated fibroblast transformation, M2 macrophage polarization, and T cell exhaustion. Gene set enrichment analysis revealed that cancer-related pathways including epithelial-to-mesenchymal transition, focal adhesion, and transforming growth factor-β (TGF-β) signaling pathways were enriched in high ANTXR1 expression tumors. Our work suggests that ANTXR1 could not only serve as a valuable prognostic biomarker in GC but also be deemed as a potential immunotherapeutic target and useful biomarker of sensitivity to chemotherapy.
Highlights
Gastric cancer (GC), imposing a considerable global health burden, is the fifth most common tumor and the third leading cause of cancer-associated death in the world (Bray et al, 2018)
Using Wilcoxon test, we further investigated the expression level of anthrax toxin receptor 1 (ANTXR1) in different clinicopathological features of GC patients and found that its level significantly correlated with T stage (P < 0.0001), AJCC stage (P < 0.001), Lauren classification (P < 0.0001), WHO grade (P < 0.05), tumor size (P < 0.05), and race (P < 0.05) based on the The Cancer Genome Atlas (TCGA) dataset (Figures 1C–H)
The results suggested that high ANTXR1 expression is significantly correlated with poor overall survival (OS) and disease-free survival (DFS) in GC patients based on TCGA cohort (Figures 2A,B), which was consistent with results obtained from the Asian Cancer Research Group (ACRG) cohort (Figures 2C,D)
Summary
Gastric cancer (GC), imposing a considerable global health burden, is the fifth most common tumor and the third leading cause of cancer-associated death in the world (Bray et al, 2018). Despite advances in screening strategies for early detection, they are neither fulfilled nor feasible in many areas of the world, leading to delayed diagnosis in most patients (Ajani et al, 2017). Targeted therapies including monoclonal antibodies against human epidermal growth factor receptor 2 (HER2) (Roviello and Generali, 2018), anti-epidermal growth factor receptor (anti-EGFR) (Maron et al, 2018), and immune checkpoint blocker such as programmed cell death protein-1 (PD-1) inhibition (Kim et al, 2018) may prolong survival in selected patients. The majority of GC patients at advanced stages, will suffer local recurrences and remote metastases after initial surgery (Niccolai et al, 2015). It is important to determine novel immunotherapeutic targets and prognostic markers of GC to shed light on the stratification of patients who may respond to immunotherapy
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Free) 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
