Abstract C109: Tumor derived exosomal lipids-induced dendritic cell immunosuppression by PPARα

Abstract

Abstract Dendritic cells (DCs), a type of professional antigen-presenting cells, play a key role in orchestrating anti-tumor immune responses. In the tumor microenvironment, tumor infiltrating DCs (TIDCs) present tumor associated antigens to effector T cells and facilitate the induction of memory T cells to prevent tumor recurrence. However, emerging evidences indicate that TIDCs become immunosuppressive with a high intracellular lipid content phenotype. TIDCs with abnormal lipid accumulation are associated with endoplasmic reticulum (ER) stress responses or increased fatty acid oxidation which also contribute to immunosuppressive. However, the critical factor inducing lipid-laden immunosuppressive TIDCs remains to be determined. Here we report: (a) In vitro, tumor derived exosomes (TDEs), isolated from tumor culture medium can directly induce lipid accumulation in DCs rather than TDE-free tumor culture medium. In vivo, we generate GFP-CD9-tumor cells to trace the receiver cells of GFP-labeled TDEs in the tumor microenvironment. The results show that TIDCs capture GFP-labeled TDEs and become lipid abundant. By treating DCs with TDEs from different tumor cell lines and of different concentrations or time, we observe that TDE-induced lipid accumulation in DCs is tumor-origin independent but time and concentration dependent. Collectively, we can conclude that TDEs are responsible for the intracellular lipid accumulation in DCs. (b) Upon internalization of TDEs, increased expression of genes involved in lipid accumulation and higher mitochondrial respiration are observed in DCs, which results in lower ability to prime tumor-specific T cell responses. (c) Then, we demonstrate that the fatty acids contained in TDEs directly contribute to lipid laden DC, rather than proteins or nucleic acids. Moreover, we identify PPARα as the key player in orchestrating both lipid metabolism and immunological features of DCs. (d) PPARα initiates both de novo lipid synthesis and fatty acids β-oxidation in DCs by sensing the excess fatty acids, which leads to immunosuppression in DCs. Pharmacological inhibitor of PPARα can overcome TDE-induced lipid accumulation, fatty acids β-oxidation and immunosuppressive function in DCs. (e) Combination therapy of PPARα pharmacological inhibitor and immunotherapy (such as the check point blocker or the therapeutic cancer vaccine) shows superior anti-tumor efficacy over monotherapy. The present study unprecedentedly provides substantial evidences that TDEs can act as a major immunosuppressive component within tumor microenvironment to undermine the proper functions of TIDCs. More importantly, we demonstrate targeting PPARα could be a potential strategy to design novel immunotherapy combinations, in order to maximize the induction, expansion and cytotoxicity of tumor-specific CD8+ T cells by restoring TIDCs function. Citation Format: Xiaozhe Yin, Wenfeng Zeng, Bowen Wu, Zihao Wang, Hongjian Tian, Luyao Wang, Luoyang Wang, Xiuli Wei, Yan Qin, Fayun Zhang, Chunling Zhang, Lingtao Jin, Wei Liang. Tumor derived exosomal lipids-induced dendritic cell immunosuppression by PPARα [abstract]. In: Proceedings of the AACR-NCI-EORTC International Conference on Molecular Targets and Cancer Therapeutics; 2019 Oct 26-30; Boston, MA. Philadelphia (PA): AACR; Mol Cancer Ther 2019;18(12 Suppl):Abstract nr C109. doi:10.1158/1535-7163.TARG-19-C109