Attenuated Toxoplasma gondii enhances the antitumor efficacy of anti-PD1 antibody by altering the tumor microenvironment in a pancreatic cancer mouse model

Purpose To investigate whether attenuated Toxoplasma is efficacious against solid tumors of pancreatic cancer and whether attenuated Toxoplasma improves the antitumor activity of alpha PD-1 antibody on pancreatic cancer. Methods The therapeutic effects of attenuated Toxoplasma NRTUA strain monotherapy and combination therapy of NRTUA with anti-PD-1 antibody on PDAC tumor volume and tumor weight of Pan02 tumor-bearing mice were investigated. We characterized the effects of combination therapy of NRTUA with anti-PD-1 antibody on tumor-infiltrating lymphocytes and tumor-specific IFN-gamma by using immunohistochemistry, flow cytometry and ELISA. The antitumor mechanisms of combination therapy of NRTUA with anti-PD-1 antibody were investigated via depletion of CD8(+) T cells and IL-12. Results NRTUA strain treatment inhibited tumor growth in a subcutaneous mouse model of PDAC through activating dendritic cells and increasing CD8(+) T cell infiltration in the tumor microenvironment. More importantly, combination therapy of NRTUA with anti-PD-1 antibody elicited a significant antitumor immune response and synergistically controlled tumor growth in Pan02 tumor-bearing mice. Specifically, the combination treatment led to elevation of CD8(+) T cell infiltration mediated by dendritic cell-secreted IL-12 and to tumor-specific IFN-gamma production in the PDAC tumor microenvironment. Also, the combination treatment markedly reduced the immunosuppressive myeloid-derived suppressor cell population in PDAC mice. Conclusion These findings could provide a novel immunotherapy approach to treating solid tumors of PDAC and overcoming resistance to anti-PD-1 agents in PDAC tumors.