Anticancer Treatment Influences TREM2 in Tumor-Associated Macrophages in Lung Cancer

Abstract

Purpose The triggering receptor expressed on myeloid cells 2 (TREM2) creates an immunosuppressive environment, but the effects of anticancer treatment on TREM2 and the tumor microenvironment (TME) are not well established. This study investigates the impact of chemotherapy on TREM2-expressing macrophages within the lung adenocarcinoma TME. Materials and Methods Using single-cell RNA sequencing datasets of paired normal-appearing lung tissue (NL) and tumor (Tu), human and mouse lung cancer tissue, and THP-1 cells, we observed the effects of anticancer drugs on them. Results Myeloid cells (MY) were the second-most abundant non-epithelial component in the Tu, though less prevalent than in NL. Specific MY subclusters abundant in Tu showed overexpression of TREM2. In lung cancer-induced Kras-G12D mice, M2 proportion increased in Tu compared to NL; cisplatin increased TREM2+ M2 proportion in Tu. TREM2+ cells in Tu showed interactions with cell clusters showing characteristics of interstitial macrophage such as mo-lineage, mono-Mc, and CD163/LGMN cells via FN:CD44 and MIF:CD74+CXCR4, suggesting that they influence the recruitment of those cells to Tu and TME reshape. In M0-state THP-1 cells, cisplatin and osimertinib treatments induced polarization towards M1 and M2 states and increased TREM2 expression. Cisplatin promoted uptake of phosphatidylserine-coated latex beads by M0 cells, whereas osimertinib reduced uptake by polarized macrophages. These findings suggest anticancer treatments impact the lung immune microenvironment by altering the TREM2+ cells. Conclusion Given TREM2's central inhibitory role in the tumor immune environment, effects of chemotherapeutic agents should be considered in developing TREM2-targeting therapies.