Microwave ablation combined with immune checkpoint inhibitor enhanced the antitumor immune activation and memory in rechallenged tumor mouse model

• Published in: Cancer Immunology, Immunotherapy : CII Vol. 74; no. 5; pp. 161 - 18
• Main Authors: Xu, Fengkuo, Sang, Jing, Wang, Nan, Wang, Meixiang, Huang, Yahan, Ma, Ji, Chen, Huanan, Xie, Qi, Wei, Zhigang, Ye, Xin
• Format: Journal Article
• Language: English
• Published: Berlin/Heidelberg Springer Berlin Heidelberg 25.03.2025; Springer Nature B.V; Springer
• Subjects: Ablation; Animal models; Animals; Antigen (tumor-associated); Antigens; Antitumor activity; Cancer Research; Carcinoma, Non-Small-Cell Lung - immunology; Carcinoma, Non-Small-Cell Lung - pathology; Carcinoma, Non-Small-Cell Lung - therapy; CD8 antigen; CD8+T cells; CD8-Positive T-Lymphocytes - immunology; Cell differentiation; Cell Line, Tumor; Combined Modality Therapy; Dendritic cells; Disease Models, Animal; Effector cells; Female; FTY720; Humans; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunologic Memory; Immunological memory; Immunology; Immunotherapy; Immunotherapy - methods; Leukocyte migration; Lung Neoplasms - immunology; Lung Neoplasms - pathology; Lung Neoplasms - therapy; Lymph nodes; Lymphatic system; Lymphocytes; Lymphocytes T; Lymphocytes, Tumor-Infiltrating - immunology; Medicine; Medicine & Public Health; Memory cells; Mice; Microenvironments; Microwave ablation; Microwaves - therapeutic use; Non-small cell lung carcinoma; Oncology; PD-L1; PD-L1 protein; Small cell lung carcinoma; Tumor cells; Tumor-infiltrating lymphocytes; PD-L1; Microwave ablation; Immune checkpoint inhibitors; Dendritic cells; T cells; CD8; CD8+T cells
• ISSN: 1432-0851; 0340-7004; 1432-0851
• DOI: 10.1007/s00262-025-04003-5

Microwave ablation (MWA) is a super minimally invasive therapeutic approach that has been widely applied in the treatment of non-small cell lung cancer (NSCLC). Although MWA can elicit antitumor immune responses, these immune responses are not relatively steady and insufficient to completely clear recurrence tumor cells within the body. Immunotherapy monotherapy has shown low clinical efficacy in the treatment of advanced NSCLC. MWA combined with immune checkpoint inhibitors (ICIs) is a promising therapeutic approach. However, the mechanism of synergic effect remains elusive. In this study, we have conducted a retrospective analysis of the clinical outcomes of MWA combined with ICIs, finding that the combinational therapy yielded superior Objective Response Rate and longer Progression-Free Survival. In preclinical models, we established a tumor rechallenged model to address post-MWA recurrence and to delve into the underlying mechanisms of the combined therapy. We observed that the combined treatment (MWA + PD-L1 blockade therapy) effectively addressed the issue of tumor recurrence in tumor rechallenged model. The combinational therapy increased the function and percentage of CD8 + tumor-infiltrating lymphocytes, enhanced the functionality of CD8 + T cells within tumor-draining lymph nodes (TdLNs), and elevated the proportion of T central memory cells. Additionally, the combined treatments promoted the proportion of Migration Dendritic Cells type 1 (Mig DC1) within TdLNs, thereby enhancing their activation potential. Notably, FTY720-mediated blockade of lymphocyte egress abolished the therapeutic benefits, confirming TdLNs-dependent systemic immunity. Moreover, the efficacy of the combinational therapy depended on the migration of T cells from TdLNs to tumor site. In summary, we proposed a potentially effective combined treatment regimen and have elucidated the underlying cellular mechanisms that underpin its efficacy. Graphical abstract After microwave ablation (MWA) of the primary tumor, the release of tumor-associated antigens (TAAs) occurs. These antigens are then internalized by Migration-Directed Dendritic Cells type 1 (Mig DC1), which subsequently migrate to the tumor-draining lymph nodes (TdLNs). Within the microenvironment of the TdLNs, Mig DC1 presents these antigens to naive T cells, prompting their differentiation into T central memory (Tcm) cells. In the context of the combined therapeutic approach, which includes MWA and PD-L1 blockade therapy, a greater number of Tcm cells are induced and activated, allowing for a rapid response to tumor re-challenge. These Tcm cells differentiate into effector T cells and migrate to the tumor site to exhibit antitumor activity.