High Dose Radiotherapy Combined With TGF-β Blocking Alleviate Cervical Cancer Cell-Suppressed Dendritic Cell Homing Through PGE2 Pathway

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By analyzing clinical samples of cervical cancer patients that did not significantly regress after radiotherapy, we found in the microenvironment the CD1a+ dendritic cells (DCs) tended to be confined within the transforming growth factor β (TGF-β) high expression area. This finding promotes us to investigate whether tumor cell-deriving TGF-β affects intratumor DC migration and homing, and most importantly, what role RT played in this process.U14 cells were chosen as a representative of cervical cancer cell. After inoculated with supernatant of radiated U14 cells, bone marrow derived DCs were analyzed for maturation and in vivo homing ability. Galunisertib and AH6809 were used as receptor antagonist to block the TGF-β and PGE2 signal on DCs, respectively. In addition, DCs were also intratumorally injected to mimic the tumor infiltrated DCs to assess their homing to tumor draining lymph nodes and T cell priming ability.TGF-β secreted by U14 cell lines was dose-dependently upregulated by radiation and significantly suppressed DC maturation, migration and cytoskeletal reorganization. Once blocking TGF-β signal, the elevated PGE2 from U14 cells induced by high dose radiation could obviously reboot cervical cancer cell-suppressed DC homing. RhoA/ROCK1/MLC signaling pathway was involved in the improved cytoskeleton organization. In addition, an improved homing ability of intratumorally injected DCs to tumor-draining lymph node (t-LN) was observed in mice receiving high dose radiation combined with intragastric administration of galunisertib. Correspondingly, a more robust T cell priming was also detected in t-LNs. Finally, based on tumor-bearing mice model, we found RT combined with galunisertib has obvious advantages over the monotherapy in promoting the intratumoral CD8+ T cell infiltration, inhibiting tumor growth and improving the overall survival rate. Of note, the simultaneously blocking PGE2 would greatly discount the improved therapeutic effect brought by RT combined with TGF-β signal blocking.The tumor deriving TGF-β significantly hindered DC migration and in vivo homing. RT combined with TGF-β signal blocking can restore the impaired homing of DCs through PGE2 pathway, and dramatically improve the anti-tumoral therapeutic effect against cervical cancer.Z. Zhou: None. F. Zhang: None. K. Hu: None.