Irreversible electroporation combined with PD-L1/IL-6 dual blockade promotes anti-tumor immunity via cDC2/CD4+T cell axis in MHC-I deficient pancreatic cancer

Pancreatic ductal adenocarcinoma (PDAC) is a "cold" solid tumor with frequent Major Histocompatibility Complex I (MHC-I) deficiency, thereby making it resistant to type-1-conventional dendritic cell (cDC1)-CD8+T cell mediated anti-tumor immunity. Current studies have demonstrated the emerging compensatory role of MHCII-mediated antigen presentation and CD4+T cell activation in anti-tumor immunity against MHC-I-deficient tumors. However, the underlying mechanism of the compensatory immune response by CD4+T cells in cancer ablation therapy remains to be elucidate. In clinical samples and murine models, we observed that irreversible electroporation (IRE) ablation therapy promoted immune infiltration and the conversion of CD4+T cells into anti-tumor IFN-gamma+Th1 cells and Th17 cells in MHC-I low-expressed PDAC using scRNA-seq and flow-cytometry analyses. Furthermore, we found that PD-L1 blockade predominantly enhanced the activation of CD11b+CD103-type-2 conventional dendritic cells (cDC2s) and their antigen presentation to CD4+T cells after ablation, stimulating the anti-tumor immune response through the tumor antigen-specific IFN-gamma+Th1-NK cell axis. Elevated plasma levels of IL-6 in pancreatic cancer patients receiving ablation therapy are significant indicators for impaired prognosis. IL-6 and PD-L1 dual blockade could significantly augment the ratio of IFN-gamma+Th1 in CD4+T cells to boost the anti-tumor immunity of NK cells, leading to prolonged survival of mouse bearing pancreatic cancer. Collectively, we have elucidated that PD-L1 blockade activates the cDC2-CD4+T cell axis after IRE therapy, thereby playing a pivotal compensatory anti-tumor role in MHC-I low-expressed pancreatic cancer. Moreover, a combination strategy involving dual-target blockade of PD-L1/IL-6 along with ablation therapy could emerge as a novel therapeutic approach for MHC-I deficient tumors.