Abstract
IntroductionCD73 is a membrane-bound enzyme crucial in adenosine generation. The adenosinergic pathway plays a critical role in immunosuppression and in anti-tumor effects of immune checkpoint inhibitors (ICI). Here, we interrogated CD73 expression in a richly annotated cohort of human lung adenocarcinoma (LUAD) and its association with clinicopathological, immune, and molecular features to better understand the role of this immune marker in LUAD pathobiology.Materials and methodsProtein expression of CD73 was evaluated by immunohistochemistry in 106 archived LUADs from patients that underwent surgical treatment without neoadjuvant therapy. Total CD73 (T +) was calculated as the average of luminal (L +) and basolateral (BL +) percentage membrane expression scores for each LUAD and was used to classify tumors into three groups based on the extent of T CD73 expression (high, low, and negative).ResultsCD73 expression was significantly and progressively increased across normal-appearing lung tissue, adenomatous atypical hyperplasia, adenocarcinoma in situ, minimally invasive adenocarcinoma, and LUAD. In LUAD, BL CD73 expression was associated with an increase in PD-L1 expression in tumor cells and increase of tumor-associated immune cells. Stratification of LUADs based on T CD73 extent also revealed that tumors with high expression of this enzyme overall exhibited significantly elevated immune infiltration and PD-L1 protein expression. Immune profiling demonstrated that T-cell inflammation and adenosine signatures were significantly higher in CD73-expressing lung adenocarcinomas relative to those lacking CD73.ConclusionOur study suggests that higher CD73 expression is associated with an overall augmented host immune response, suggesting potential implications in the immune pathobiology of early stage lung adenocarcinoma. Our findings warrant further studies to explore the role of CD73 in immunotherapeutic response of LUAD.
Highlights
CD73 is a membrane-bound enzyme crucial in adenosine generation
Formalin-fixed paraffin-embedded (FFPE) lung adenocarcinoma (LUAD) tissue was placed in a tissue microarray (TMA); the tumor samples were selected based on the availability of FFPE tissue blocks; three 1 mm-diameter cores that included tissue from the center, intermediate, and peripheral areas of the tumor were used for the TMA, as previously described [24]
We found that CD73 was expressed in a significant fraction (75%) of LUADs and categorized subsets of LUAD with distinct histological, molecular, and immune features
Summary
Despite significant improvements in treatment, lung cancer remains the leading cause of cancer-related deaths worldwide [1]. Immune checkpoint inhibitors (ICI), as a single agent or in combination with chemotherapy, are increasingly becoming the standard treatment for non-small cell lung cancer (NSCLC), including advanced-stage lung adenocarcinoma (LUAD) [2,3,4,5]. Tumor microenvironment (TME) immunosuppression has emerged as a sentinel mechanism in lung cancer progression and, a viable phenotypic target for treatment [17, 18]. In this context, numerous therapeutic approaches are currently under development with the goal of skewing the TME toward an immune effective phenotype [19]. We demonstrate that the extent of CD73 expression in malignant cells (MCs) defines groups of LUADs with distinct immune profiles and that may guide future personalized immunotherapeutic strategies
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