Abstract
Irreversible electroporation (IRE) is a new cancer ablation technology, but methods to improve IRE-induced therapeutic immunity are only beginning to be investigated. We developed a mouse model bearing large primary (300 mm3) and medium distant (100 mm3) EG7 lymphomas engineered to express ovalbumin (OVA) as a nominal tumor antigen. We established experimental protocols including IRE alone and IRE combined with Toll-like receptor (TLR)3/9 agonists (poly I:C/CpG) (IRE + pIC/CpG), PD-1 blockade (IRE + PD-1 blockade), or both (IRE + Combo) to investigate therapeutic effects on primary and distant EG7 tumors and conversion-promoting effects on the immunotolerant tumor microenvironment (TME). We demonstrated that IRE alone simulated very weak OVA-specific CD8+ T cell responses and did not inhibit primary tumor growth. IRE + pIC/CpG synergistically stimulated more efficient OVA-specific CD8+ T cell responses and primary tumor growth inhibition than IRE + PD-1 blockade. IRE + pIC/CpG played a major role in the modulation of immune cell profiles but a minor role in the downregulation of PD-L1 expression in the TME and vice versa for IRE + PD-1 blockade. IRE + Combo cooperatively induced potent OVA-specific CD8+ T cell immunity and rescued exhausted intratumoral CD8+ T cells, leading to eradication of not only primary tumors but also untreated concomitant distant tumors and lung metastases. IRE + Combo efficiently modulated immune cell profiles, as evidenced by reductions in immunotolerant type-2 (M2) macrophages, myeloid-derived suppressor-cells, plasmacytoid dendritic cells, and regulatory T cells and by increases in immunogenic M1 macrophages, CD169+ macrophages, type-1 conventional dendritic cells, and CD8+ T cells, leading to conversion of immunotolerance in not only primary TMEs but also untreated distant TMEs. IRE + Combo also showed effective therapeutic effects in two breast cancer models. Therefore, our results suggest that IRE + Combo is a promising strategy to improve IRE ablation therapy in cancer.
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Acknowledgements
This work was supported by grants to J.X. from the Saskatchewan Cancer Agency (SCA), Saskatchewan Health Research Foundation (SHRF), College of Medicine Research Awards (CoMRAD), Royal University Hospital Foundation (RUHF) and Prostate Cancer Fight Foundation (PCFF). F.B. and A.X. were supported by the Lisa Rendall Breast Cancer Graduate Student Scholarship and Postdoctoral Fellowship, respectively, from the SCA.
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JX conceived the project and designed the experiments. JX and AX analyzed data and wrote the manuscript. FB, JW, and AX performed experiments and organized data. ZW provided technical help. WZ and BZ provided the custom-made IRE device. R.C. and Y.W. provided technical help related to histopathology and immunohistochemistry. SA, AF, MM and GG interpreted results and reviewed the manuscript.
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Babikr, F., Wan, J., Xu, A. et al. Distinct roles but cooperative effect of TLR3/9 agonists and PD-1 blockade in converting the immunotolerant microenvironment of irreversible electroporation-ablated tumors. Cell Mol Immunol 18, 2632–2647 (2021). https://doi.org/10.1038/s41423-021-00796-4
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DOI: https://doi.org/10.1038/s41423-021-00796-4
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