Immunologic Strategies in Pancreatic Cancer: Making Cold Tumors Hot

Abstract

The rising incidence and persistent dismal 5-year overall survival of pancreatic ductal adenocarcinoma (PDAC) highlight the need for new effective systemic therapies. Immunotherapy has shown significant benefits in solid organ tumors, but has thus far been disappointing in the treatment of PDAC. There have been several promising preclinical studies, but translation into the clinic has proved to be challenging. This is likely a result of PDAC's complex immunosuppressive tumor microenvironment that acts to insulate the tumor against an effective cytotoxic immune response. Here, we summarize the mechanisms of immunosuppression within the PDAC tumor microenvironment and provide an up-to-date review of completed and ongoing clinical trials using various immunotherapy strategies.

FIG 1.

PDAC-intrinsic immunoevasive properties. APC, antigen-presenting cell; CAF, cancer-associated fibroblasts; DC, dendritic cell; GM-CSF, granulocyte-macrophage colony-stimulating factor; HLA-DR, human leukocyte antigen-DR isotype; IDO, indoleamine 2,3-dioxygenase; IL, interleukin; KYN, kynurenine; MDSCs, myeloid-derived suppressor cells; MHC-1, major histocompatibility complex-1; PD-1, programmed death-1; PDAC, pancreatic adenocarcinoma; PD-L1, programmed death ligand-1; SIRPα, signal regulatory protein alpha; TAM, tumor-associated macrophages; TCR, T-cell receptor; Treg, regulatory T-cell; TRP, tryptophan.

FIG 2.

The highly immunosuppressive tumor microenvironment of pancreatic ductal adenocarcinoma. Pancreatic tumor cells, myeloid cells (Mo-MDSCs, TAMs, and Gr-MDSCs), and fibroblasts within the tumor microenvironment interact through various ligands, cytokines, and chemokines that disrupt antitumor immunity. CAF, cancer-associated fibroblasts; GM-CSF, granulocyte-macrophage colony-stimulating factor; Gr-MDSC, granulocytic MDSC; IL, interleukin; MDSC, myeloid-derived suppressor cell; Mo-MDSC, monocytic MDSC; PD-L1, programmed death ligand-1; PDAC, pancreatic ductal adenocarcinoma; TAM, tumor-associated macrophage; TGF, transforming growth factor; Treg, regulatory T-cell; VEGF, vascular endothelial growth factor.