Abstract 6839: Comprehensive transcriptomic analysis of acquired resistance after immune-checkpoint inhibitors in non-small cell lung cancer

Abstract

Abstract Background: Treatment of lung cancer has changed dramatically with the use of immune checkpoint inhibitors (ICI). Nevertheless, most patients underwent drug resistance even though they initially showed a response to ICI, and there is an unmet need to delineate the mechanism. Method: We analyzed RNA sequencing data of paired pre- and post-ICI samples from 31 NSCLC patients. Among them, we identified 17 patients who underwent acquired resistance (AR) who initially showed partial or complete response or stable disease lasting more than six months, and the remaining 14 patients who showed primary resistance (PR) to ICI. The analysis was performed using a tumor microenvironment (TME) classifier, classifying immune-enriched [IE], immune-enriched and fibrotic [IE/F], fibrotic [F] and immune-desert [D] subtype, and CIBERSORTx, the immune cell deconvolutional analysis tool. Results: Most patients with AR were initially classified as IE or IE/F subtypes (N=12, 70.6%), but six out of 14 with PR (42.8%) showed IE or IE/F subtypes. Among 12 patients with initial IE or IE/F subtypes, seven (58.3%) patients turned into the D subtype after AR to ICI. Most patients initially classified as D or F subtypes (N=5, 29.4%) maintained their subtypes (N=4, 80%) after AR.When assessing the pre-ICI samples, memory B cell was enriched, and M2 macrophage and regulatory T cell were depleted in AR patients compared to PR. The memory B cell and resting memory CD4+T cell decreased, and M2 macrophage increased after AR to ICI. These immune cell composition changes were not observed in PR patients. Conclusions: We observed differences in TME phenotype and immune cell composition before ICI between AR & PR patients. The TME change from immune-enriched to desert and cell composition change of increased M2 macrophages and decreased memory B and resting CD4+ T cells after AR to ICI could be significant mechanisms of AR to ICI. Citation Format: Cheol Yong Joe, Yeong Hak Bang, Sehhoon Park, Hyun Ae Jung, Jong-Mu Sun, Yoon-La Choi, Jin Seok Ahn, Myung-Ju Ahn, Se-Hoon Lee. Comprehensive transcriptomic analysis of acquired resistance after immune-checkpoint inhibitors in non-small cell lung cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 6839.