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Figure 2. Mechanisms of pancreatic cancer resistance to immune-checkpoint inhibitor therapy. Pancreatic ductal adenocarcinoma is known as a tumor with a "cold" microenvironment characterized by a small number of CD8+ T- and NK cells, an abundance of regulatory T (immunosuppressive) cells, and poor response to ICI therapy. Mutation in KRAS gene (mKRAS) allows pancreatic cancer cells to induce expression of granulocyte-macrophage colony-stimulating factor (GM-CSF), chemokine C-X-C motif ligand 1 (CXCL1) and C-C motif chemokine ligand 4 (CCL4) playing a crucial role in immunosuppression. Moreover, mKRAS leads to upregulation of WNT/β -catenin pathway and Sonic Hedgehog pro-inflammatory pathways overall, inhibiting the ICI therapy.