Background: Although immunotherapy yields striking results in various malignancies, results in pancreatic cancer have been disappointing. Both a highly immunosuppressive tumor microenvironment and a dense desmoplastic stroma have been found to prohibit proper T-cell infiltration in these tumors, thereby preventing immunotherapy efficacy. We hypothesize that a rational and translational multistep approach is needed to sensitize pancreatic cancer to immunotherapy. In an aggressive murine pancreatic ductal adenocarcinoma model, we assessed the effectiveness of dendritic cell (DC) vaccination in combination with αCD40 treatment, as these treatments are known to induce effector T cells and degrade stroma, respectively.
Methods: Immune competent C57BL/6 mice were inoculated subcutaneously with pancreatic tumor cells (KPC3). Mice with established tumors were vaccinated with tumor-loaded monocyte derived DCs and consequently treated with αCD40 agonistic antibodies. Tumor sizes were monitored over time. Immune responses were determined by flow cytometry of cells in peripheral blood, spleen and tumor. NanoString Technologies were applied on tumor samples.
Results: A significant delay in tumor growth was found in the combination therapy arm compared to untreated mice and mice treated with DCs or αCD40 alone. Monotherapy had no effect on tumor growth. Survival of mice treated with the combination therapy was also improved compared to untreated mice or mice treated with monotherapy (P < 0.001). Interim blood analysis showed significant increases in frequencies of activated and proliferating T cells in treated animals and those cells also displayed an effector memory phenotype. This was more pronounced for CD4 T cells in mice treated with DCs while αCD40 therapy induced a confined response in CD8 T cells. Increased frequencies of tumor infiltrating lymphocytes were found in all treated mice compared to untreated mice. mRNA expression analysis indicated less exhausted phenotype of intratumoral lymphoid cells in mice treated with DCs and αCD40 compared to monotherapy DCs or αCD40.
Conclusions: These results demonstrate the potency of this novel form of combination immunotherapy and reveals a mechanistic insight into the requirements of effective immunotherapy in pancreatic cancer.