Background: CD73, known as ecto-5’-nucleotidase and encoded by the NT5E gene, is a pivotal enzyme that converts extracellular adenosine monophosphate (AMP) into adenosine, which promotes tumor growth by impairing anti-tumor T cell immunity. Several preclinical studies noted that the pharmacologic inhibition of CD73 led to improved immune response and thus highlighted the value of CD73 as a therapeutic target for cancer immunotherapy. Methods: CD73 expression was explored from The Cancer Genome Atlas (TCGA) database including patients with adenocarcinoma (n = 517) and squamous cell carcinoma (n = 501) of the lung. We stratified samples based on mRNA expression level (low, low-intermediate, intermediate-high, high). Immune profiling (immune cell infiltration, immune checkpoints, and cytokines), tumor mutational burden (TMB), neoantigen burden, and survival outcome were analyzed between the CD73 high group (CD73-H) and CD73 low group (CD73-L). The tumor immune landscape was analyzed using the signatures derived from 812 ‘immune metagenes’ that predict the immune infiltration of 31 distinct immune cells for each tumor sample (Angelova, M. et al, 2015). Results: In NSCLC, CD73-H showed significantly lower infiltration of activated CD4 and CD8 T cells compared with CD73-L (41% vs 20%, P< 0.01; 47% vs 28%, P< 0.01 respectively). In addition, PD-L1 (CD274), ICOS, TGFB1, and IL1B expression positively correlated with CD73 expression. However, TMB and neoantigen burden demonstrated no significant differences between the two groups. CD73-H had significantly shorter overall survival (OS) and disease free survival (DFS) compared with CD73-L (OS median 62 vs 44 months, P< 0.01; DFS median 83 vs 34 months, P< 0.01). Additionally, CD73 expression was significantly increased in samples with EGFR mutations when compared with wild type (mean z-score 0.77 vs -0.06, P= 0.03). Conclusions: This is the first report to illustrate an inverse association between CD73 expression and tumor infiltration of activated CD4 and CD8 T cells, as analyzed in over 1,000 human lung cancer samples. In addition, CD73-H demonstrated unfavorable survival outcome compared with CD73-L. CD73 remains a promising target for cancer immune modulation.