Abstract 916: Tumor extracellular vesicles trigger a dendritic cell stress response to promote immune evasion and immunotherapy resistance
Wang, M; Plebanek, M; Villarreal, K; DeVito, NC; Theivanthiran, B; Hanks, BA
Published in: Cancer Research
Previous studies have demonstrated dendritic cell (DC)-mediated T cell activation to be impaired within the tumor microenvironment (TME). This has included studies showing that activation of XBP1 within the unfolded protein response (UPR) pathway triggers lipid accumulation by DCs within the TME, however the signal mediating XBP1 activation has remained unclear. We have previously demonstrated that fatty acid oxidation (FAO) as well as the activation of the SREBP2-dependent mevalonate biosynthetic pathway leads to the development of mregDCs in the TME, exhibiting impaired antigen cross-presentation and an enhanced capacity to drive regulatory T cell (Treg) differentiation. Despite the critical role of the DC in orchestrating anti-tumor immunity, there are currently no therapeutic strategies to augment their function. Using an autochthonous model of BRAFV600E melanoma, we demonstrate that tumor-dependent generation of extra-cellular vesicles (ECVs) suppresses anti-tumor immunity and supports tumor progression. Using bulk and single-cell RNA sequencing analysis, we show that tumor ECVs upregulate various components of the UPR pathway in conventional DCs (cDCs), including IRE1alpha-XBP1 and SREBP2 activation based on qPCR and Western blot studies. We further show that XBP1 activation leads to PPARalpha nuclear translocation and enhanced FAO. We verify that lymph node DC populations engulfing labeled tumor ECVs harboring a CD81-GFP fusion protein also exhibit both enhanced XBP1/PPARalpha activation as well as the transcriptional signature of mregDCs. Together, these ECV-dependent effects suppress DC-mediated antigen cross-presentation and CD8+ T cell activation while promoting DC-dependent Treg differentiation in vitro and in vivo. Additional studies were conducted showing similar effects generated by ECVs derived from models of colon and breast cancer. We subsequently found DC-specific knock-out of PPARalpha to partially reverse the effects of tumor ECVs on DC functionality in an engineered transgenic murine model. Indeed, a PPARalpha antagonist, TPST-1120, overcomes resistance to anti-PD-1 immunotherapy in a poorly immunogenic autochthonous melanoma model while suppressing DC lipid stores and DC FAO in situ. Together, this work suggests that pharmacologic targeting of pathways elicited by tumor-derived ECVs can reverse DC tolerization in the TME and overcome immunotherapy resistance in select tumors. Understanding which tumors rely on ECVs to suppress anti-tumor immunity will be a critical step in prospectively developing targeted therapeutics to block these immune evasive pathways and enhance the efficacy of checkpoint inhibitor immunotherapy.
