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Background <p>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.</p> Methods <p>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<sub>OVA</sub> (BL<sub>OVA</sub>) melanoma model.</p> Results <p>We demonstrated that inclusion of the CD40-agonist in the IRE + Combo treatment regimen promoted a more robust CD8<sup>+</sup> 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<sub>OVA</sub> melanoma in 5/8 of BL<sub>OVA</sub>-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<sup>+</sup>CD103<sup>+</sup> 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<sup>+</sup>TCF1<sup>+</sup> tissue-resident memory T (T<sub>RM</sub>) cells (32.1%) in TDLNs when compared with the two control (15.3% and 6.7%) treatment groups, and that these T<sub>RM</sub> 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.</p> Conclusion <p>Taken together, this study establishes that the CD40-agonist greatly potentiates the efficacy of IRE-ablation for metastatic melanoma by promoting unexpected CD8<sup>+</sup>CD103<sup>+</sup> cDC1 and CD103<sup>+</sup>TCF1<sup>+</sup> T<sub>RM</sub> cell responses and suggests the importance of targeting CD40-signaling to improve the efficacy of cancer IRE-ablation therapy.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年11月18日

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  • 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

摘要

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 BL6-10OVA (BLOVA) 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 BLOVA melanoma in 5/8 of BLOVA-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 (TRM) cells (32.1%) in TDLNs when compared with the two control (15.3% and 6.7%) treatment groups, and that these TRM 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+ TRM cell responses and suggests the importance of targeting CD40-signaling to improve the efficacy of cancer IRE-ablation therapy.