Immune-suppressive microenvironment was revealed from NSCLC patients with hyperprogressive disease (HPD) from immunotherapy.

Abstract

e21109 Background: Immune checkpoint inhibitors (ICIs) demonstrated clear survival benefit in advanced non-small cell lung cancer (NSCLC) and was considered as a standard treatment. However, 10%-20% of ICI treated patients presented hyper-progressive disease (HPD) and shortened OS (< 5 months). In this study, we analyzed the tumor immune microenvironment (TME) of HPD and non-HPD NSCLC patients, aiming to reveal their discrepancies. Methods: Advanced NSCLC patients treated with ICIs in West China Hospital from March 2015 to January 2020 were retrospectively analyzed. HPD was defined as: 1) RECIST progression at first response evaluation, or time-to-treatment failure (TTF) < 2 months; 2) increase in tumor volume > 50%; 3) tumor growth rate (TGR) > 2-fold. Total cellular RNA was extracted from FFPE samples and subjected to gene expression evaluation using NanoString nCounter. A customized code set consisting of a 289-gene panel related to the tumor, immune regulation, and tumor microenvironment was used. Results: A total of 296 patients were screened, including 26 (8.8%) HPD and 272 (91.2%) non-HPD patients. A total of 52 specimens were subjected to TME analysis. At last, data from 27 (8 HPD and 19 non-HPD) samples were suitable for final analysis. We revealed 22 differential expressed genes (DEGs) (fold change > = 2, FDR < 0.05) in the HPD group using DESeq2, including 14 up-regulated genes and 8 down-regulated genes. Gene ontology (GO) enrichment analysis revealed that the DEGs were significantly enriched in leukocyte migration, leukocyte chemotaxis, and neutrophil migration. The Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis results revealed that the DEGs were significantly enriched in IL-17 signaling pathway. Levels and proportions of 16 immune cell types, tumor-infiltrating lymphocytes (TILs) score, cytolytic activity (CYT) score, cytotoxic T lymphocytes (CTL) level, IFN-γ signature, T cell markers, teff score and 18-gene T cell-inflamed GEP score were estimated using characteristic gene expression signatures. We found that immune cells had a lower tendency in the HPD group, and B-cells, CD45, cytotoxic cells, T-cells, and Th1-cells reached significantly lower levels. Further analysis revealed that the HPD group had significantly lower total TILs score, Teff score, and T cell-inflamed GEP score. Conclusions: HPD patients in NSCLC had immune-suppressive TME which were significantly different from non-HPD patients. Patients with low TILs score, Teff score, and T cell-inflamed GEP score may develop HPD and have a poor prognosis after receiving ICIs therapy. The TME signatures in the tissues before ICIs treatment might become a predictive biomarker of HPD risk.