Project description:Pancreatic cancer (PC) is a devastating disease characterised by late diagnosis, genetic neoplastic heterogeneity, poor T-cell infiltration, a highly immunosuppressive tumour microenvironment, and metastatic spreading which results in poor clinical outcomes. Surgery remains the most effective treatment, although it is limited to a few patients. Local ablative techniques, such as radiofrequency ablation (RFA), have been proposed to control PC progression in patients with nonresectable tumours. However, the impact of these therapies on promoting the activation of the immune system and eliciting an effective anti-tumour immune response remains elusive. Whether local ablative techniques could overcome resistance to immunotherapy in PC is unknown. We enrolled a cohort of patients with non-resectable locally advanced pancreatic cancer and longitudinally evaluated the impact of local thermal ablation on circulating immunological parameters. Additionally, we used cancer cell lines derived from PC transgenic mouse models to establish a preclinical platform that recapitulates systemic and localised inflammation induced by RFA in vivo. Finally, we employed this preclinical experimental platform to evaluate the efficacy of the therapeutic treatments. Thermal ablation induced a short-term inflammatory process resulting in a systemic increase in myeloid cells as well as increased plasma levels of high mobility group box 1 molecule, which correlates with a better patient outcome. We performed thermal ablative procedures in mice bearing orthotopic PC and evaluated the therapeutic efficacy of thermal treatment alone or in combination with immune checkpoint-based immunotherapy through activation of a T lymphocyte-dependent anti-tumour immune response. We demonstrated that RFA synergises with immunotherapy to restrict tumour progression, significantly improving the overall survival of PC-bearing mice. Tumour immune landscape characterisation confirmed that RFA in combination with immunotherapy supported the sculpting of an immune hostile milieu towards an effective anti-tumour milieu characterised by an increased infiltration of cytotoxic T lymphocytes in spite of CD206-expressing tumour-associated macrophages. Our study confirmed that RFA enhances immunotherapy effectiveness by breaking tumour immune tolerance and unleashing the full cytotoxic abilities of tumour-specific T-cells. Thus, RFA can circumvent the current limitations of immunotherapy in patients with pancreatic cancer.
Project description:Pancreatic ductal adenocarcinoma rapidly acquires resistance to chemotherapy, remaining a fatal disease. Immunotherapy is one of the breakthroughs in cancer treatment, which includes immune checkpoint inhibitors, chimeric antigen receptor T-cell immunotherapy, and neoantigen vaccines. However, immunotherapy has not achieved satisfactory results in the treatment of pancreatic cancer. Immunogenic death comprises proinflammatory cell death, which provides a way to enhance tumor immunogenicity and promote an immune response in solid tumors. Herein, an ionic liquid ablation agent (LAA), synthesized from choline and geranic acid, which triggers necrosis-induced immunotherapy by remodeling an immunosuppressive "cold" tumor to an immune activated "hot" tumor is described. The results indicate that LAA-treated tumor cells can enhance immunogenicity, inducing dendritic cell maturation, macrophage M1 polarization, and cytotoxic T lymphocyte infiltration. The results of the present study provide a novel strategy for solid tumor immunotherapy.
