TMPs Induce TREM2+ TAM-mediated Progression of Malignant Pleural Effusion and Package Etomoxir for Targeted Therapy

Abstract Rationale: Malignant pleural effusion (MPE) is an exemplary research model of tumor immune microenvironment. TREM2+ tumor-associated macrophages (TAM) contribute to the formation of an immunosuppressive tumor milieu and the progression of the tumor. However, the precise factors inducing TREM2+ TAM formation and the mechanisms underlying their immunosuppressive effects remain unclear. Objectives: To elucidate the mechanism underlying the role of TREM2+ TAM in MPE and explore targeted therapy. Methods: Distribution and correlation of EpCAM+ microparticles, TREM2+ TAM and CD8+ T cells in MPE, tuberculous pleural effusion (TPE) and blood from patients were determined. The effects and mechanisms of tumor derived microparticles (TMPs) on differentiation of TREM2+ TAM were explored. The impacts and mechanisms TREM2+ TAM on tumor immune microenvironment were also investigated. TMPs packaging Etomoxir (UV-TMPs-Eto) was synthesized and the effects of UV-TMPs-Eto on TREM2+ TAM and MPE progression were investigated. Measurements and main results: The numbers of EpCAM+ MPs and TREM2+ TAM were increased while CD8+ T cells was decreased in MPE when compared with TPE from patients. The increased TREM2+ TAM was partially attributed to the fatty acids abundant in TMPs. By enhancing fatty acid oxidation, the TREM2+ TAM curtailed the proliferation and cytotoxic activity of CD8+ T cells and led to the progression of MPE. UV-TMPs-Eto could inhibit the progression of MPE by counteracting the immunosuppressive TREM2+ TAM phenotype and activating the antitumor CD8+ T and NK cells through targeted fatty acid oxidation inhibition. Conclusions: We revealed novel mechanism of TREM2+ TAM-mediated progression of MPE, and synthesized UV-TMPs-Eto for targeted therapy.