ERAP2 Is Associated With Immune Infiltration and Predicts Favorable Prognosis in SqCLC

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.

Variation in ERAP2 has opposing effects on severe respiratory infection and autoimmune disease

“…One potential explanation is environmental-and/or time-specific selection, whereby in times of high pathogen pressure there is strong evolutionary pressure to increase gene expression of ERAP2, but this is counterbalanced at other times by negative consequences (e.g., Crohn disease, type 1 diabetes). Previous literature has identified that changes in ERAP2 expression are associated with changes in survival from cancer, although one study identified increased survival 43 with increased ERAP2 expression, and the other decreased survival, 44 while there are known genetic associations such as psoriasis 45 and juvenile idiopathic arthritis 29 at this locus. Additionally, the association with birdshot chorioretinopathy is dependent upon an interaction with HLA, further complicating analyses.…”

A Comparative Review of Pregnancy and Cancer and Their Association with Endoplasmic Reticulum Aminopeptidase 1 and 2

“…ERAP1 and ERAP2 are potential anti-cancer targets activating immune responses against malignant cancers by promoting T and NK cell-mediated cytotoxic responses [ 86 ]. One study noted that a higher expression of ERAP2 in the immunoreactive tumor microenvironment of Squamous-cell lung cancer (SqCLC) patients is correlated with high levels of immune markers and cells that include PD-L1, CD47, CD8+ TIL, CD68+ macrophages, and NK cells, which are all positive indicators for immunotherapy [ 87 ]. ERAP1 expression furthers the cancer progression, such as in cervical carcinoma.…”

ERAP2 as a potential biomarker for predicting gemcitabine response in patients with pancreatic cancer

“…ERAP2 has previously been considered a homologue of placental leucine aminopeptidase/insulin-regulated aminopeptidase [23][24][25], but its function has not been thoroughly studied. Recent studies report that ERAP2 is an oncogenic gene, overexpressed in variant cancers, such as glioblastoma, choriocarcinoma and oral cavity squamous cell carcinoma (OSCC) [26][27][28][29]. ERAP2 overexpression has been reported to benefit cervical metastasis, resulting in a poor prognosis of OSCC [30].…”