The CXCL10/CXCR3 Pathway Contributes to the Synergy of Thermal Ablation and PD-1 Blockade Therapy against Tumors

SIMPLE SUMMARY: Thermal ablation has been confirmed to increase the percentage of functional CD8(+)T cells in the tumor microenvironment (TME) and activate tumor-specific T cells via the enhancement of tumor antigen presentation to the immune system. However, its underlying mechanism remains largely unclear. Herein, we demonstrated that the interaction between macrophages and effector CD8(+)T cells through the CXCL10/CXCR3 pathway in the TME contributed essentially to the therapeutic effect of a combined strategy and improved the synergistic effect of this combination therapy of thermal ablation and PD-1 blockade against tumors. ABSTRACT: As a practical local therapeutic approach to destroy tumor tissue, thermal ablation can activate tumor-specific T cells via enhancing tumor antigen presentation to the immune system. In the present study, we investigated changes in infiltrating immune cells in tumor tissues from the non-radiofrequency ablation (RFA) side by analyzing single-cell RNA sequencing (scRNA-seq) data of tumor-bearing mice compared with control tumors. We showed that ablation treatment could increase the proportion of CD8(+)T cells and the interaction between macrophages and T cells was altered. Another thermal ablation treatment, microwave ablation (MWA), increased the enrichment of signaling pathways for chemotaxis and chemokine response and was associated with the chemokine CXCL10. In addition, the immune checkpoint PD-1 was especially up-regulated in the infiltrating T cells of tumors on the non-ablation side after thermal ablation treatment. Combination therapy of ablation and PD-1 blockade had a synergistic anti-tumor effect. Furthermore, we found that the CXCL10/CXCR3 axis contributed to the therapeutic efficacy of ablation combined with anti-PD-1 therapy, and activation of the CXCL10/CXCR3 signaling pathway might improve the synergistic effect of this combination treatment against solid tumors.