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

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

doi:10.1007/s00262-025-04217-7

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

Cancer Immunol Immunother. 2025 Nov 18;74(12):378. doi: 10.1007/s00262-025-04217-7.

Authors

Zhaojia Wu^#^{1

2}, Zhenyu Yang^#^{1

2

3}, Tauqeer Iftikhar^#^{1

2}, Gary Groot⁴, Scot C Leary⁵, Nicolas Baniak⁶, Shahid Ahmed^{1

2}, Mark Bosch^{1

2}, Michael Moser⁴, Wenjun Zhang⁷, Junhong Jiang⁸, Jim Xiang^{9

10}

Affiliations

¹ Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada.
² Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada.
³ Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, China.
⁴ Department of Surgery, University of Saskatchewan, Saskatoon, SK, Canada.
⁵ Department of Biochemistry, Microbiology and Immunology, University of Saskatchewan, Saskatoon, SK, Canada.
⁶ Department of Pathology, University of Saskatchewan, Saskatoon, SK, Canada.
⁷ Division of Biomedical Engineering, University of Saskatchewan, Saskatoon, SK, Canada.
⁸ Department of Respiratory and Critical Care Medicine, The Fourth Affiliated Hospital of Soochow University, Suzhou, China. jiangjunhong1969@suda.edu.cn.
⁹ Saskatoon Cancer Center, Saskatchewan Cancer Agency, Saskatoon, SK, Canada. jim.xiang@usask.ca.
¹⁰ Department of Oncology, University of Saskatchewan, Saskatoon, SK, Canada. jim.xiang@usask.ca.

^# Contributed equally.

Abstract

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.

Keywords: CD103+ TRM cell; CD40-agonist; CD8+CD103+ cDC1; IRE-ablation; Metastatic melanoma; PD-1 blockade.

MeSH terms

Animals
Antigens, CD / immunology
Antigens, CD / metabolism
CD40 Antigens* / agonists
CD8-Positive T-Lymphocytes* / immunology
Cell Line, Tumor
Dendritic Cells* / immunology
Electroporation* / methods
Female
Humans
Integrin alpha Chains / metabolism
Melanoma* / immunology
Melanoma* / pathology
Melanoma* / therapy
Melanoma, Experimental* / immunology
Melanoma, Experimental* / therapy
Mice
Mice, Inbred C57BL
Skin Neoplasms* / immunology
Skin Neoplasms* / pathology
Skin Neoplasms* / therapy

Substances

CD40 Antigens
alpha E integrins
Integrin alpha Chains
Antigens, CD

Abstract

MeSH terms

Substances

Grants and funding