Abstract
Huntingtin-interacting protein 1-related protein (HIP1R) plays an important role in the regulation of programmed death-ligand 1 (PD-L1). The aim of this study was to investigate the expression of HIP1R and confirm its predictive or prognostic roles in anti-PD-1 therapy in nonsmall cell lung cancer (NSCLC) patients. HIP1R and PD-L1 immunohistochemical expression was examined in 52 refractory advanced NSCLC patients treated with anti-PD-1 inhibitors. We performed gene set enrichment analysis (GSEA) to detect HIP1R-specific gene sets. Patients in the PD-1 inhibitor responder group had lower HIP1R expression by univariate logistic regression analysis (odds ratio (OR) = 0.235, p = 0.015) and multivariate logistic regression analysis (OR = 0.209, p = 0.014). Patients with high HIP1R expression had poorer progression-free survival (PFS) than patients with low HIP1R expression in univariate analysis (p = 0.037) and multivariate Cox analysis (hazard ratio = 2.098, p = 0.019). The web-based mRNA dataset also showed that high HIP1R expression correlated with inferior overall survival in lung adenocarcinoma (p = 0.026). GSEA revealed that HIP1R levels correlate with a set of genes that reflect PD-L1-related immune pathways. HIP1R expression may be a promising predictor for determination of patient responses to anti-PD-1 treatment.
Highlights
Emergence of immune checkpoint inhibitors was a turning point in the treatment of advanced nonsmall cell lung cancer (NSCLC)
IL-6 is positively correlated with programmed death ligand-1 (PD-L1) expression in human hepatocellular carcinoma (HCC) cells, and IL-6 induces PD-L1 stability through glycosylation in a HCC cell line [22]
Glioblastoma-derived IL6 is required for up-regulation of myeloid PD-L1 in glioblastoma through a STAT3-dependent mechanism [23]
Summary
Emergence of immune checkpoint inhibitors was a turning point in the treatment of advanced nonsmall cell lung cancer (NSCLC). Therapies targeting the programmed cell death protein 1 (PD-1) checkpoint, such as nivolumab and pembrolizumab, have yielded impressive responsive rates in advanced NSCLC patients otherwise refractory to multiples lines of therapy [1,2,3]. Expression of programmed death ligand-1 (PD-L1), the PD-1 ligand, is currently the most widely used biomarker for PD-1 inhibition. To identify patients who preferentially respond to PD-1 blockade, we need to better understand how the PD-1 pathway is regulated. CKLF-like MARVEL transmembrane-domain-containing 6 (CMTM6) regulates the PD-1 pathway by maintaining the expression of PD-L1, and CMTM6 is a predictor of the response to PD-1 inhibitors [5,6]. AXL expression displays a positive correlation with PD-L1 expression in lung adenocarcinoma with epidermal growth factor receptor (EGFR) mutation, and abolition of AXL kinase activity inhibits PD-L1 mRNA expression in a lung adenocarcinoma cell line with EGFR mutation [8]
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