Inhibition of TFEB promotes tumor-educated dendritic cells activation to enhance antitumor immune responses

Abstract

Tumors can induce the generation and accumulation of immunosuppressive cells in -the tumor microenvironment (TME). Among them, tumor-educated dendritic cells (TEDCs) involved in tolerance induction contribute greatly to the progression of tumors. However, the mechanisms governing the immunosuppressive function of dendritic cells in the TME are unclear. In this study, we found that the expression of transcription factor EB (TFEB) was significantly increased in TEDCs induced by cancer cell supernatant. TFEB knockdown significantly promoted the differentiation and maturation of TEDCs, with upregulated expression of CD11c and costimulatory molecules (CD86 and MHC-II) but reduced expression of the inhibitory molecule PD-L1, and enhanced their ability to induce Th1 proliferation and differentiation. Moreover, TEDCs with TFEB knockdown significantly reduced tumor growth with increased infiltration of CD11c⁺MHC-II⁺ dendritic cells and effector T cells in tumor masses, thus leading to a delay in tumor progression. These findings demonstrate a critical role of TFEB in regulating the immunosuppression of TEDCs, with potential implications as an antitumor immune therapeutic approach.

Keywords: Dendritic cells; Immune response; TFEB; Tumor microenvironment.