Journal Article

CD40 agonist improves the therapeutic efficacy of irreversible electroporation ablation for metastatic melanoma by promoting unexpected CD8+CD103+ cDC1 and TRM cell responses

Wu, Zhaojia, Yang, Zhenyu, Jiang, Junhong, Groot, Gary, Leary, Scot C., Iftikhar, Tauqeer, Ahmed, Shahid, Bosch, Mark, Zhang, Wenjun, Baniak, Nicolas, Moser, Michael, Xiang, Jim

2025

Overview

Background Melanoma is one of the deadliest forms of skin cancer. Irreversible electroporation (IRE) is an innovative, non-thermal ablation technology for treating irresectable solid cancers. However, most IRE treatments are incapable of cancer eradication and only temporarily prolong patient survival. Methods In this study, we developed a novel IRE + Combo treatment regimen that combines IRE-ablation with Combo-adjuvant [CpG, anti-PD-L1 antibody (PD-L1-Ab) and CD40-agonist] and investigated its anti-tumor immunity in a mouse BL6-10 OVA (BL OVA ) melanoma model. Results We demonstrated that inclusion of the CD40-agonist in the IRE + Combo treatment regimen promoted a more robust CD8 + T cell response (6.89%) when compared with IRE + CpG/PD-L1-Ab (2.67%) or IRE alone (0.21%) treatments, leading to eradication of subcutaneous BL OVA melanoma in 5/8 of BL OVA -bearing mice and simultaneous elimination of lung melanoma metastases. Addition of CD40-agonist to the IRE + Combo treatment regimen also induced a higher frequency (17.1%) of CD8 + CD103 + conventional type-1 dendritic cells (cDC1s) with up-regulated expression of CD54, CD80, MHC II, Bcl-xL and 41BBL in tumor-drainage lymph nodes (TDLNs) relative to the control IRE + CpG/PD-L1-Ab (12.1%) and IRE alone (9.0%) treatment groups. We also show that CD40-agonist stimulated a higher frequency of CD103 + TCF1 + tissue-resident memory T (T RM ) cells (32.1%) in TDLNs when compared with the two control (15.3% and 6.7%) treatment groups, and that these T RM cells exhibited enhanced mitochondrial content and greater relative expression of the effector cytokines IFN-γ and TNF-α and the transcriptional regulators TRAF1, p38-MAPK and PGC-1α. Conclusion Taken together, this study establishes that the CD40-agonist greatly potentiates the efficacy of IRE-ablation for metastatic melanoma by promoting unexpected CD8 + CD103 + cDC1 and CD103 + TCF1 + T RM cell responses and suggests the importance of targeting CD40-signaling to improve the efficacy of cancer IRE-ablation therapy.

• Publisher: Springer Berlin Heidelberg,Springer Nature B.V,Springer
• Subject: Ablation / Agonists / Animals / Antigens, CD - immunology / Antigens, CD - metabolism / Apoptosis / Bcl-x protein / Bone marrow / Cancer Research / Cancer therapies / CD103 antigen / CD103+ TRM cell / CD40 antigen / CD40 Antigens - agonists / CD40-agonist / CD8 antigen / CD8+CD103+ cDC1 / CD8-Positive T-Lymphocytes - immunology / CD80 antigen / Cell Line, Tumor / Dendritic cells / Dendritic Cells - immunology / Electroporation / Electroporation - methods / Eradication / Female / Flow cytometry / Hepatocyte nuclear factor 1 / Humans / Immunology / Immunotherapy / Integrin alpha Chains - metabolism / IRE-ablation / Kinases / Lymph nodes / Lymphatic drainage / Lymphocytes / Lymphocytes T / Lymphoma / Major histocompatibility complex / MAP kinase / Medical research / Medicine / Medicine & Public Health / Melanoma / Melanoma - immunology / Melanoma - pathology / Melanoma - therapy / Melanoma, Experimental - immunology / Melanoma, Experimental - therapy / Metastases / Metastasis / Metastatic melanoma / Mice / Mice, Inbred C57BL / Oncology / PD-1 blockade / PD-L1 protein / Skin cancer / Skin Neoplasms - immunology / Skin Neoplasms - pathology / Skin Neoplasms - therapy / Tumor necrosis factor-TNF / Tumor necrosis factor-α / Tumors / γ-Interferon