Eric Zhao1,2, Zhaojia Wu1,2, Jianbo Yuan1,2, Shahid Ahmed2 and Jim Xiang1,2
1Department of Discovery and Translational Research, Saskatchewan Cancer Agency, Saskatoon, Saskatchewan S7N 4H4, Canada
2Department of Oncology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan S7N 5E5, Canada
Irreversible electroporation (IRE) is a relatively new, non-thermal ablation technology for cancer treatment that requires further optimization to maximize its therapeutic efficacy. To improve IRE-ablation, we developed an IRE+Combo-treatment regimen that includes Combo adjuvants [poly-I:C (pIC)/CpG, anti-PD-L1 antibody (PD-L1-Ab) and 41BB-agonist], and evaluated it in a mouse 3LLOVA lung cancer model. We demonstrated that IRE+Combo enhanced CD8+ T-cell responses (5.3%) compared to two control-groups [lacking 41BB-agonist (3.0%) and IRE alone (0.4%)], resulting in eradication of subcutaneous 3LLOVA in 75% of mice with simultaneous elimination of lung metastases. Flow cytometry analyses indicated that adding 41BB-agonist to IRE+Combo-ablation stimulated a higher frequency of CD8+CD103+ conventional type-1 dendritic cells (cDC1) (14.4%) in tumor-drainage lymph-nodes (TDLNs) relative to two controls(7.5% and 4.0%), a subset with high expression of maturation markers and costimulatory molecules (4-1BBL/4-1BB). It also stimulated 41BB+CD103+TCF-1+ tissue-resident memory T (TRM) cells (14.5%) in TDLNs (vs. 2.6% and 0.3%). Importantly, the IRE+Combo-treatment was more efficient at converting the immunosuppressive tumor microenvironment (TME) by reducing inhibitory myeloid-derived suppressive cells, increasing cDC1 and CD8+ T-cells and rescuing T-cell exhaustion in TME. Overall, the 41BB-agonist potentiates the efficacy of IRE+Combo-therapy by promoting cDC1 and TRM cell responses, highlighting its potential to improve cancer IRE-ablation strategies.
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