Eric Zhao^1,2, Zhaojia Wu^1,2, Jianbo Yuan^1,2, Shahid Ahmed²and Jim Xiang^1,2

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 3LL_OVA 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 3LL_OVA 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 (T_RM) 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 T_RM cell responses, highlighting its potential to improve cancer IRE-ablation strategies.

Articles in process

41BB signaling promotes cDC1 and TRM cell responses and modulation of tumor microenvironment in irreversible electroporation ablation-induced eradication of lung cancer