Therapeutic Potential of Targeting Stromal Crosstalk-Mediated Immune Suppression in Pancreatic Cancer

Abstract

The stroma-rich, immunosuppressive microenvironment is a hallmark of pancreatic ductal adenocarcinoma (PDA). Tumor cells and other cellular components of the tumor microenvironment, such as cancer associated fibroblasts, CD4⁺ T cells and myeloid cells, are linked by a web of interactions. Their crosstalk not only results in immune evasion of PDA, but also contributes to pancreatic cancer cell plasticity, invasiveness, metastasis, chemo-resistance, immunotherapy-resistance and radiotherapy-resistance. In this review, we characterize several prevalent populations of stromal cells in the PDA microenvironment and describe how the crosstalk among them drives and maintains immune suppression. We also summarize therapeutic approaches to target the stroma. With a better understanding of the complex cellular and molecular networks in PDA, strategies aimed at sensitizing PDA to chemotherapy or immunotherapy through re-programing the tumor microenvironment can be designed, and in turn lead to improved clinical treatment for pancreatic cancer patients.

Keywords: T cells; cancer-associated fibroblasts; immune suppression; myeloid cells; pancreatic cancer; tumor microenvironment.

Figure 1

Tumor epithelial cells modulate immunosuppressive tumor microenvironment through oncogenic pathways and immune checkpoint pathways in PDA. CCL, C-C motif chemokine ligand; CXCL, C-X-C motif chemokine ligand; ERK, extracellular signal-regulated kinase; G-CSF, granulocyte-colony stimulating factor; GDF-15, growth/differentiation factor-15; GM-CSF, granulocyte-macrophage colony-stimulating factor; ICAM-1, intercellular adhesion molecule 1; MDSCs, myeloid-derived suppressor cells; MEK, mitogen−activated protein kinase kinase; NF-κB, nuclear factor kappa B; PD-1, anti-programmed cell death 1; PD-L1, programmed cell death ligand 1; PVR, poliovirus receptor; TAMs, tumor associated macrophages; TGF-β, transforming growth factor β; TIGIT, T cell immunoreceptor with Ig and ITIM domains; Tregs, regulatory T cells; USP22, ubiquitin specific peptidase 22.

Figure 2

The dynamic cellular and molecular interactions between T cells and myeloid cell subsets in pancreatic cancer. DC, dendritic cell; IL, interleukin; MDSCs, myeloid-derived suppressor cells; NO, nitric oxide; TAMs, tumor associated macrophages; TGF-β, transforming growth factor β; Th, T helper; Tregs, regulatory T cells.

Figure 3

Crosstalk between tumor associated fibroblasts and other TME components within pancreatic cancer. CAF, cancer associated fibroblasts; CCL, C-C motif chemokine ligand; CXCL, C-X-C motif chemokine ligand; DC, dendritic cell; HH, hedgehog; IL, interleukin; MDSCs, myeloid-derived suppressor cells; TAMs, tumor associated macrophages; TGF-β, transforming growth factor β; Tregs, regulatory T cells; VEGF, vascular endothelial growth factor.

Figure 4

Current active clinical trials targeting immunosuppressive TME in pancreatic cancer. CAF, cancer associated fibroblasts; CCL, C-C motif chemokine ligand; CCR, C-C motif chemokine receptor; CSF1R, colony-stimulating factor 1 receptor; CXCL, C-X-C motif chemokine ligand; DC, dendritic cell; IL, interleukin; MDSCs, myeloid-derived suppressor cells; PD-1, anti-programmed cell death 1; PD-L1, programmed cell death ligand 1; TAMs, tumor associated macrophages; TGF-β, transforming growth factor β; Th, T helper; Tregs, regulatory T cells.