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Distinct roles but cooperative effect of TLR3/9 agonists and pd-1 blockade in converting the immunotolerant microenvironment of irreversible electroporation-ablated tumors

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Cellular & Molecular Immunology 2021年第12期18卷 2632-2647页

作者： Fatma Babikr Jiangbo Wan Aizhang Xu Zhaojia Wu Shahid Ahmed Andrew Freywald Rajni Chibbar Yue Wu Michael Moser Gary Groot Wenjun Zhang Bing Zhang Jim Xiang Saskatoon Cancer Center Saskatchewan Cancer AgencySaskatoonSKCanada Department of Oncology University of SaskatchewanSaskatoonSKCanada Department of Hematology Xinhua HospitalAffiliated to Shanghai Jiao Tong University School of MedicineShanghaiChina Department of Pathology University of SaskatchewanSaskatoonSKCanada Department of Surgery University of SaskatchewanSaskatoonSKCanada Department of Bioengineering University of SaskatchewanSaskatoonSKCanada Biomedical Science and Technology Research Center Shanghai UniversityShanghaiChina

Irreversible electroporation(IRE)is a new cancer ablation technology,but methods to improve IRE-induced therapeutic immunity are only beginning to be *** developed a mouse model bearing large primary(300 mm^(3))and medium distant(100 mm^(3))EG7 lymphomas engineered to express ovalbumin(OVA)as a nominal tumor *** 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 ***+pIC/CpG synergistically stimulated more efficient OVA-specific CD8^(+)T cell responses and primary tumor growth inhibition than IRE+pd-1 ***+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 ***+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 ***+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 ***+Combo also showed effective therapeutic effects in two breast cancer ***,our results suggest that IRE+Combo is a promising strategy to improve IRE ablation therapy in cancer.

关键词： IRE ablation TLR3/9-agonists pd-1-blockade CD8+T-cell response antitumor immunity

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