Fig. 1

Mechanisms of immune resistance to checkpoint blockade in pancreatic cancer. Preclinical evidence supports that combinatorial strategies incorporating checkpoint inhibitors can attenuate primary and acquired resistance to checkpoint blockade through multiple tumor cell-intrinsic and tumor cell-extrinsic mechanisms. For example, targeting of H3K4 trimethylation, JAK/STAT signaling, and mitogen-activated protein kinase (MAPK) signaling mitigates tumor cell-intrinsic upregulation of PD-L1 expression. Combination regimens with checkpoint blockade can also target tumor cell-extrinsic mechanisms of immune resistance by decreasing tumor-associated macrophages (TAMs) or reprogramming TAMs to increase antigen presentation and antitumor T-cell activity. MDSCs myeloid-derived suppressor cells, APCs antigen-presenting cells, MHC major histocompatibility complex, TCR T-cell antigen receptor, PD-1 programmed cell death protein 1 receptor, B7 B7 family of ligands, TILs tumor-infiltrating lymphocytes, PD-L1 programmed death ligand 1, CTLA-4 cytotoxic T-lymphocyte associated protein 4, IFNγ interferon-γ, IL-2 interleukin 2, TNF-α tumor necrosis factor alpha, Tregs regulatory T-cells