Interferon-gamma (INFG), an important marker of response to immune checkpoint blockade (ICB) in non-small cell lung cancer (NSCLC) and melanoma patients.

Abstract

11504 Background: PD-L1 can be induced by oncogenic signals or up-regulated via INFG in a STAT1- and NFκB-dependent manner. STAT3 opposes STAT1-mediated anti-tumor immune responses. I kappa B kinase epsilon (IKBKE) is an interferon signaling inducer. We explored whether INFG expression in pre-treatment tumors is associated with to the efficacy of ICB in NSCLC and melanoma patients. The role of inflammation-associated transcription factors STAT3, IKBKE and STAT1 was also examined. Methods: Total RNA from 17 NSCLC and 21 melanoma patients, was analyzed by qRT-PCR. INFG, STAT3, IKBKE, STAT1 and PD-L1 mRNA were examined. PD-L1 protein expression in tumor and immune cells was evaluated (Ventana SP142 assay). Progression free survival (PFS) and overall survival (OS) were estimated. Results: 17 previously treated NSCLC patients received nivolumab; 71% lung adenocarcinoma, 71% male, 53% smokers, 35% KRAS mutant, 88% EGFR wild-type (wt). 21 previously treated melanoma patients received pembrolizumab; 67% male, 67% BRAF wt. PFS to nivolumab was significantly longer in NSCLC patients with high vs. low INFG expression (5.12 vs. 2mo, p = 0.0124). PFS to pembrolizumab was significantly longer in melanoma patients with high vs. low INFG expression (4.99 vs. 1.86mo, p = 0.0099). Significantly longer OS was observed for melanoma patients with high vs. low INFG expression (not reached vs. 3.10mo p = 0.0183). There was a trend for longer OS for NSCLC patients with high vs. low INFG expression (10.15 vs. 4.86mo, p = 0.0687). The other gene levels and PD-L1 protein levels in tumor and immune cells did not affect the outcome to ICB. IKBKE was positively correlated with INFG and PD-L1 expression (NSCLC Spearman’s ρ = 0.58 and 0.65; melanoma Spearman’s ρ = 0.61 and 0.59), and STAT3 expression was loosely anticorrelated with PD-L1 expression (NSCLC Spearman’s ρ = −0.21; melanoma Pearson’s ρ = −0.01). Conclusions: INFG is an important marker for qRT-PCR mediated prediction of response to ICB in NSCLC and melanoma patients. Further research is warranted in order to validate that INFG is more accurate than PD-L1.