Abstract
BackgroundImmunotherapy has been proven effective among several human cancer types, including Squamous cell lung carcinoma (SqCLC). ERAP2 plays a pivotal role in peptide trimming of many immunological processes. However, the prognostic role of ERAP2 and its relationship with immune cell infiltration in SqCLC remains unclear.MethodsThe differential expression of ERAP2 was identified via GEO and TCGA databases. We calculated the impact of ERAP2 on clinical prognosis using the Kaplan-Meier plotter. TIMER was applied to evaluate the abundance of immune cells infiltration and immune markers. SqCLC tissue microarrays containing 190 patients were constructed, and we performed immunohistochemical staining for ERAP2, CD8, CD47, CD68, and PD-L1 to validate our findings in public data.ResultsIn the GEO SqCLC database, ERAP2 was upregulated in patients with better survival (p=0.001). ERAP2 expression in SqCLC was significantly lower than that of matched normal samples (p<0.05) based on TCGA SqCLC data. Higher expression of ERAP2 was significantly associated with better survival in SqCLC patients from TCGA (p=0.007), KM-plotter (p=0.017), and our tissue microarrays (TMAs) (p=0.026). In univariate and multivariate Cox analysis of SqCLC TMAs, high ERAP2 expression was identified as an independent protective factor for SqCLC patients (Univariate Cox, HR=0.659, range 0.454-0.956, p<0.05. Multivariate Cox, HR=0.578, range 0.385-0.866, p<0.05). In TIMER, ERAP2 was positively correlated with several immune markers (CD274, p=1.27E-04; CD68, p=5.88E-08) and immune infiltrating cells (CD8+ T cell, p=4.09E-03; NK cell, p=1.00E-04). In our cohort, ERAP2 was significantly correlated with CD8+ tumor-infiltrating lymphocytes (TILs) (p=0.0029), and patients with higher ERAP2 expression had a higher percentage of PD-L1 positive patients (p=0.049) and a higher CD8+ TILs level (p=0.036).ConclusionsFor the first time, our study demonstrates that higher expression of ERAP2 is tightly associated with the immuno-supportive microenvironment and can predict a favorable prognosis in SqCLC. Meanwhile, ERAP2 may be a promising immunotherapeutic target for patients with SqCLC.
Highlights
According to the newest data published in 2021, lung cancer has the highest mortality rate among all cancer types and is a significant health care concern throughout the world [1]
Different from lung adenocarcinoma (LUAD), which has greatly benefited from targeted therapies against driver mutations such as epidermal growth factor receptor (EGFR) mutations, etc., inroads in targeted therapy are rare in squamous cell lung cancer (SqCLC) [6, 7]
We found that ERAP2 expression in SqCLC was statistically lower than that in paired normal tissues (Figure 1C), suggesting that the deficiency of ERAP2 might participate in the carcinogenesis of SqCLC
Summary
According to the newest data published in 2021, lung cancer has the highest mortality rate among all cancer types and is a significant health care concern throughout the world [1]. Over the past few decades, the limited therapeutic options rendered SqCLC a challenging-to-treat disease. The introduction of immunotherapy, blockers of the PD-1 axis, into the treatment of NSCLC has revolutionized the therapeutic stand-care of this recalcitrant disease, yielding significant survival benefits [8]. Only a minority of SqCLC patients have achieved sustained benefits. The immunotherapy of SqCLC is still in its infancy, and more immune-related treatments are warranted. Immunotherapy has been proven effective among several human cancer types, including Squamous cell lung carcinoma (SqCLC). The prognostic role of ERAP2 and its relationship with immune cell infiltration in SqCLC remains unclear
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