PATZ1 in Non-Small Cell Lung Cancer: A New Biomarker That Negatively Correlates with PD-L1 Expression and Suppresses the Malignant Phenotype

SIMPLE SUMMARY: Lung cancer is the leading cause of cancer death worldwide. Most lung cancers are classified as non-small cell lung cancer (NSCLC), which is diagnosed at an advanced stage when various treatments cannot be curative. Immunotherapy is a promising treatment for many cancers, including NSCLC, and the big challenge is the identification of new tumor biomarkers able to predict its success. In this framework, the aim of our study was to evaluate the expression of PATZ1, an emerging cancer-related protein suggested as a diagnostic marker in different cancers, in correlation with the expression of PD-L1, a major target of immunotherapy, in NSCLC. Our analysis, conducted in different NSCLC tumor samples and two NSCLC cell lines, indicated that PATZ1 and PD-L1 expressions are negatively associated and that PATZ1 overexpression downregulates PD-L1 expression. Furthermore, we show that deletion or halving of PATZ1 expression induces NSCLC in mice, whereas overexpression of PATZ1 in NSCLC cells reduces their ability to proliferate, migrate, and invade, compared to controls, suggesting that PATZ1 functions as a suppressor of NSCLC. ABSTRACT: Non-small cell lung cancer (NSCLC), the leading cause of cancer death worldwide, is still an unmet medical problem due to the lack of both effective therapies against advanced stages and markers to allow a diagnosis of the disease at early stages before its progression. Immunotherapy targeting the PD-1/PD-L1 checkpoint is promising for many cancers, including NSCLC, but its success depends on the tumor expression of PD-L1. PATZ1 is an emerging cancer-related transcriptional regulator and diagnostic/prognostic biomarker in different malignant tumors, but its role in lung cancer is still obscure. Here we investigated expression and role of PATZ1 in NSCLC, in correlation with NSCLC subtypes and PD-L1 expression. A cohort of 104 NSCLCs, including lung squamous cell carcinomas (LUSCs) and adenocarcinomas (LUADs), was retrospectively analyzed by immunohistochemistry for the expression of PATZ1 and PD-L1. The results were correlated with each other and with the clinical characteristics, showing on the one hand a positive correlation between the high expression of PATZ1 and the LUSC subtype and, on the other hand, a negative correlation between PATZ1 and PD-L1, validated at the mRNA level in independent NSCLC datasets. Consistently, two NSCLC cell lines transfected with a PATZ1-overexpressing plasmid showed PD-L1 downregulation, suggesting a role for PATZ1 in the negative regulation of PD-L1. We also showed that PATZ1 overexpression inhibits NSCLC cell proliferation, migration, and invasion, and that Patz1-knockout mice develop LUAD. Overall, this suggests that PATZ1 may act as a tumor suppressor in NSCLC.