The Immune Checkpoint CD73 (NT5E) in Gastric Adenocarcinoma (GAC): Biological Characterization and Clinical Implications.

235 Background: CD73, an ecto-5’-nucleotidase (NT5E), serves as an immune checkpoint by generating adenosine, which in turn leads to immune-suppression and immune-escape. Elevated tissue levels of CD73 have been linked to poor patient survival across several cancer types and CD73 blockade is currently being tested in clinical trials. The biological role of CD73 and its translational relevance is largely unexplored in gastric adenocarcinoma (GAC). Methods: Data mining from transcriptomics big data sources including GEPIA2, HPA and Coexpedia platforms was performed to extract relevant information regarding CD73 expression profile, co-expressed network, association with clinico-pathologic features and survival of GAC. Difference between groups were evaluated by Student's t-test, while correlation analysis was performed through Pearson’s coefficient. Kaplan-Meier methods was used to estimate survival and log-rank test to make comparison between curves. Results: RNA sequencing expression data of 9,736 tumors and 8,587 normal tissue samples from the TCGA and the GTEx projects were analyzed. CD73 mRNA was significantly more expressed in tumour (n = 408) compared to paired normal samples (n = 211) (16.19 vs 3.5 transcripts/million; p < 0.001) and its expression level increased with pathologic stage (from stage I to III). CD73 gene was listed among the top-ten survival-associated genes (p = 4.74e-5) in GAC and together with FGF1 it displayed the greatest survival contribution in this disease among clinically validated genes. Regarding its impact on survival, GAC patients with high CD73 expression (n = 192) experienced a poorer overall survival (OS) compared to the low CD73 group (n = 192) (HR 1.9; log-rank p < 0.001), while regarding relapse-free survival (RFS), the unfavourable value of CD73 expression emerged after 20 months (HR 1.3; log-rank p = 0.23). The prognostic role on OS was validated in a cohort of 354 GAC, where high CD73 expression resulted in 5-year OS of 19% vs 46% (p = 0.00010). When inquiring for context-associated co-expression networks, Caveolin 1 (score = 10.939), FOS-like antigen 1 (score = 7.525) and plasminogen activator urokinase receptor (score = 7.422) were top-ranked co-expressed genes. Conclusions: In this hypothesis-generating analysis, we provided insights into CD73 expression pattern, co-expression networking and prognostic significance in GAC. Future studies in clinically annotated populations are warranted to confirm the value of CD73 in GAC.