Abstract 171: Chemotherapeutic agent, cisplatin, influences the proportion of TREM2 (+) M2 macrophages in the TME of LUAD

Abstract Background: Triggering receptor expressed on myeloid cells (TREM2) serves as an immune signaling hub that senses and interacts with a wide range of ligands arising from damaged tissues in pathologic conditions. Despite TREM2’s diverse role in casting immune suppressive environment, the effects of chemotherapy on tumor microenvironment (TME), TREM2 and their interactions are not well established. In this study, we aimed to investigate the characteristics of TREM2 (+) Mφ within the lung TME (Tu), focusing on the impact of chemotherapy on the immune dynamics of lung adenocarcinoma (LUAD). Method: Changes in the number and distribution of Mφ subclusters in normal appearing lung tissue (NL) and Tu were examined using open-source single cell RNA sequencing (scRNA-seq) datasets and immunofluorescent staining of lung cancer-induced Kras-G12D mouse tissue. Clinical measures affecting the expression of TREM2 were explored using the TCGA-LUAD and -LUSC datasets, and the effects of anticancer drugs and the apoptotic cells on Mφ were observed by differentiating THP1 cells into M0, M1, and M2. Results: scRNA-seq analysis on LUAD datasets showed that Mφ were the second most abundant cell population that constitutes the lung TME, and the proportion of Mφ in the Tu decreases compared to NL. Among the Mφ subclusters in Tu, a subcluster which specifically increased in Tu shows enrichment of apoptotic cell clearance gene sets, including TREM2. In lung cancer induced Kras-G12D mouse, compared to NL the Tu has an increase in M2 proportion, showing the characteristics of interstitial Mφ in addition with overexpression of TREM2 and enrichment of monocyte chemotaxis gene set enrichment. Among TCGA-LUAD, the high TMB group has low TREM2 expression, and the proportion of TREM2 (+) M2 in the Tu decreases in cisplatin-treated Kras-G12D mouse Tu, suggesting the expression of TREM2 in M2 is suppressed by either cisplatin treatment itself or active immunity in Tu. Additionally, we are going to observe the effect on TREM2 expression by adding cisplatin treated A549-GFP cells or cisplatin alone, to the THP-1 cells that were differentiated into M0, M1, or M2 state. Conclusion: In addition to changes in the lung immune environment due to the tumor, anticancer treatment changes in the characteristics of M2 in TME, in terms of decrease in TREM2 (+) Mφ fraction. Considering that TREM2 plays a central inhibitory role in the tumor immune environment, the effect of anticancer chemotherapeutic agents should be considered in the development TREM2 targeting agents. Citation Format: Yoon Jin Cha, Min Kyung Park, Yoon Soo Chang. Chemotherapeutic agent, cisplatin, influences the proportion of TREM2 (+) M2 macrophages in the TME of LUAD [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 171.