P12.05 Neutrophil Elastase as Combined Immunotherapy Target for Treating NSCLC

Abstract

Immunotherapy has emerged as a promising option for treating non-small cell lung cancer (NSCLC). However, immunotherapy is not equally effective for all patients. Drug resistance is also a big hurdle in treatment. Recently, cancer immune microenvironment has proved of great significance for immunotherapy. Neutrophil elastase, a protease able to degrade several extracellular matrix proteins, is encoded by ELANE gene. neutrophil elastase (NE) and neutrophil dominate airway inflammation. Sivelestat is the only approved drug working as a selective NE inhibitor. However, their direct impact on the tumor immune microenvironment is not clear. The goal of this study, therefore, was to investigate the the effects of ELANE on the NSCLC microenvironment, and the application potential of sivelestat on combination therapies to enhance the efficacy of immune checkpoint inhibitors. The relationship between ELANE and tumor-infiltrated immune cells was analyzed using TIMER. Immunohistochemistry was used to evaluate the density of, CD8+TILs, and CD163+ macrophages. NE from peripheral blood of NSCLC patients was determined by ELISA. The mouse model and flow cytometry were used to investigate the effects of sivelestat on the tumor-infiltrating immune cells and the efficacy of immune checkpoint inhibitors. ELANE was significantly positively correlated with the proportion of M2 macrophages, and negatively associated the proportion of CD8+TILs. NE levels in peripheral blood of NSCLC patients was significantly positively correlated with the density of CD163+ macrophages, and negatively associated the density of, CD8+TILs. Sivelestat, which had already been marketed as a selective NE inhibitor, could increase CD8+ infiltration and reduced M2 macrophage infiltration. It can also improve the efficacy of immune checkpoint inhibitors in the mouse model. NE levels in peripheral blood could be used as potential biomarker that may predict sensitivity to immunotherapy. Sivelestat，as a selective NE inhibitor already marketed，can potentially be harnessed in combination with immune checkpoint inhibitors to increase the efficacy of immunotherapy.