Background: CD73, an ecto-5’-nucleotidase (NT5E), creates an immunosuppressive tumour-promoting microenvironment by converting ATP to adenosine. The expression of CD73 has been linked to poorer patients (pts) outcome across several cancer types and the targeted inhibition of this immunoinhibitory protein has been recently advanced to clinical development. However, the clinicopathologic role of CD73 as well as its potential implications are largely unexplored in BC. Methods: The expression of CD73 was assessed by immunohistochemistry on both tumour (tCD73) and stromal tissue (sCD73) of a clinically-annotated cohort of radically-resected BC and scored for staining intensity as follows: +1, +2 and +3. RNAseq was performed on RNA isolated from surgical specimens. Differences between groups were evaluated using the Chi-square test. Survival functions were estimated by the Kaplan-Meier method and comparisons were made using the log-rank test. The Cox proportional hazards model was used to assess the impact of covariates on survival outcomes. Results: CD73 immunohistochimichal expression was evaluated on resected specimens of 70 BC pts. 43 pts (61%) were tCD73-positive, while 44 pts (62%) were sCD73-positive. Among the former group, the intensity score was 1+ in 19 pts (44%), 2+ in 16 pts (37%), 3+ in 10 pts (23%), while in the latter group was 1+ in 22 pts (50%), 2+ in 10 pts (22%) and 3+ in 12 pts (27%). CD73 positivity was associated with older age (> 70 years, p = 0.01), gallbladder subsite (p = 0.03), and nodal involvement (p = 0.04). Patients with tCD73-positive BC experienced a significantly shorter relapse-free survival (8,4 vs 39,4 months; p = 0.016) and overall survival (60,7 vs 13,7 months; p = 0.017). Notably, high tCD73 expressors (score 3+) displayed the poorest prognosis (12,03 months; p = 0.023). When evaluated on univariate and multivariate analysis, tCD73 positivity was an independent prognostic factor for both relapse-free survival (p = 0.038) and overall survival (p = 0.023), together with ECOG PS and pTNM stage. Whole-transcriptome sequencing is ongoing to correlate CD73 expression with cancer-related pathways. Conclusions: In this study, we provided a clinicopathologic characterization of CD73 expression in resected BC, demonstrating that tCD73 is an independent negative prognostic biomarker in this disease. Although these findings are in need of a validation in larger dataset, they foster novel combination of anti-CD73 agents with conventional therapy in the poorer-prognosis subset of CD73-positive BC.

Clinicopathologic correlates and prognostic relevance of the immune checkpoint CD73 (NT5E) in resected biliary cancers (BC)

Antonella Iuliano;
2022-01-01

Abstract

Background: CD73, an ecto-5’-nucleotidase (NT5E), creates an immunosuppressive tumour-promoting microenvironment by converting ATP to adenosine. The expression of CD73 has been linked to poorer patients (pts) outcome across several cancer types and the targeted inhibition of this immunoinhibitory protein has been recently advanced to clinical development. However, the clinicopathologic role of CD73 as well as its potential implications are largely unexplored in BC. Methods: The expression of CD73 was assessed by immunohistochemistry on both tumour (tCD73) and stromal tissue (sCD73) of a clinically-annotated cohort of radically-resected BC and scored for staining intensity as follows: +1, +2 and +3. RNAseq was performed on RNA isolated from surgical specimens. Differences between groups were evaluated using the Chi-square test. Survival functions were estimated by the Kaplan-Meier method and comparisons were made using the log-rank test. The Cox proportional hazards model was used to assess the impact of covariates on survival outcomes. Results: CD73 immunohistochimichal expression was evaluated on resected specimens of 70 BC pts. 43 pts (61%) were tCD73-positive, while 44 pts (62%) were sCD73-positive. Among the former group, the intensity score was 1+ in 19 pts (44%), 2+ in 16 pts (37%), 3+ in 10 pts (23%), while in the latter group was 1+ in 22 pts (50%), 2+ in 10 pts (22%) and 3+ in 12 pts (27%). CD73 positivity was associated with older age (> 70 years, p = 0.01), gallbladder subsite (p = 0.03), and nodal involvement (p = 0.04). Patients with tCD73-positive BC experienced a significantly shorter relapse-free survival (8,4 vs 39,4 months; p = 0.016) and overall survival (60,7 vs 13,7 months; p = 0.017). Notably, high tCD73 expressors (score 3+) displayed the poorest prognosis (12,03 months; p = 0.023). When evaluated on univariate and multivariate analysis, tCD73 positivity was an independent prognostic factor for both relapse-free survival (p = 0.038) and overall survival (p = 0.023), together with ECOG PS and pTNM stage. Whole-transcriptome sequencing is ongoing to correlate CD73 expression with cancer-related pathways. Conclusions: In this study, we provided a clinicopathologic characterization of CD73 expression in resected BC, demonstrating that tCD73 is an independent negative prognostic biomarker in this disease. Although these findings are in need of a validation in larger dataset, they foster novel combination of anti-CD73 agents with conventional therapy in the poorer-prognosis subset of CD73-positive BC.
2022
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Utilizza questo identificativo per citare o creare un link a questo documento: https://hdl.handle.net/11563/175595
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