CD169-positive macrophages enhance abscopal effect of radiofrequency ablation therapy in liver cancer

Radiofrequency ablation (RFA) is a widely used and effective treatment for primary or metastatic liver cancer with small-size lesions. However, the therapeutic effectiveness of RFA in controlling metastatic lesion or recurrence is still limited. As the major cell population in tumor microenvironment (TME), macrophages have been reported to be recruited to RFA-treated lesion, but their roles are still unclear. Herein, we successfully established the mouse model mimicking RFA-induced abscopal effect, in which RFA eliminated the local orthotopic liver tumor but failed to control growth of distant tumor. Correspondently, RFA suppressed protumoral activation of local tumor-associated macrophages (TAMs), but failed to reprogram TAMs in distance. Importantly, although RFA led to reduced proportion of hepatic CD169⁺ macrophages in local and decreased expression of immune inhibitory molecules Tim-3 and PD-L1, these alterations were not observed for CD169⁺ macrophages in distant TME. Further RNA-seq and flow cytometry analysis showed that hepatic CD169⁺ macrophages contributed to reprograming TME through recruiting CD8⁺ T/NK cells and suppressing accumulation of MDSCs/Tregs. Consistently, depletion of CD169⁺ macrophages in CD169-DTR mouse greatly promoted liver tumor progression and largely dampened RFA-induced tumor suppression. Notably, transfer of CD169⁺ macrophages synergistically enhanced RFA-induced inhibition of distant tumor. To our knowledge, this is the first study which demonstrates hepatic CD169⁺ macrophages as a key factor responsible for RFA-induced abscopal effect. Our data suggest RFA with transfer of CD169⁺ macrophages as a promising combination therapy to lessen metastasis or recurrence of liver cancer in patients.