Table 1.

The effect of stromal components in pancreatic TME on cancer immunosuppression.

Stromal cells	Recruitment & activation	Stromal cell-derived substances	Target cells	Effect on immune response	Ref.
MDSCs	CSF, VEGF, IL, CXCL, TGF-β, TNF-α, IFN-γ, PEG-2	iNOS, arginase, TGF-β, ROS, COX2, IDO, IL-6 and IL-10	NK cells, CD4+ and CD8+ T, Tregs	Inhibition of lymphocyte activity, recruitment of Tregs and expression of immunosuppressive checkpoint molecules	(11–33)
CAFs	Differentiated from fibroblasts, MSCs, adipocytes and PSCs	IL-6, TGF-β, CCL, CXCL, MCP-1, PGE2, IDO,	Tregs, CD8+ T, TAMs, NK cells, tumor cells	Recruitment of Tregs and MDSCs, inhibiting T cells and NK cells activity, and increasing PD-L1 expression	(3, 34–44)
Treg cells	CXCL10, CXCR3-CCL9/10/11, CCR4-CCL17/22 and CCR8-CCL1	TCF-β, CTLA4, IL-10, PD-L1, MADCAM-1, VCAM-1, granzyme B and perforin	NK cells, CD8+ T, Th cells, and APCs	Inhibiting the function of immune cells, secreting immunosuppressive cytokines and inducing apoptosis of NK cells,	(45–52)
TAMs	CCL, CXCL, VEGF, TLR4, IL-4, IL-13,	IFN-γ, TNF, iNOS, MHCII, ARG1, IL-10, PGE2, EGF, EGFR, IL-10, TGF-β CD163 and CD204	Tumor cells, CD8+ T, Tregs	Inducing Treg differentiation, inhibiting T cells function, producing inhibitory cytokines, increasing the CTLA-4 and PD-1 expression	(53–63)
PSCs	interleukin and TGF-β,	IL-10, CXCL12, MCP-1, VEGF, fibronectin and type I collagen	Immune cells, tumor cells, TAMs, MDSCs,	promoting differentiation and migration of MDSCs and TAMs, leading to imbalance of Th1/Th2 cytokines	(64–68)
TANs	CXCL, TGF-β, IFN-β and GM-CSF	IL-13, CCL17, CCL2, ARG1, elastase and MMP9	Tregs, CAFs, and TAMs	Promoting TAMs polarization, recruitment of Tregs, up-regulating ARG1 and PD-1	(69–72)
DCs	Recruitment is inhibited by PGE2	CD80, CD40, CD70, CD86, MHC-I, MHC-II, IFN-γ, IL-12, IL-15, MGL2 and PD-L2.	T cells, Tregs, Th17.	Impairment of DC activation, maturation and antigen presentation; Inducing the proliferation of Treg cells and inhibiting CD8+ T cell- immunity; regulating the balance between Th17 and Treg cells.
NK cells	HLA-G, CD47, CCL5/CCR5, CCL27/CCR10, CX3CL1/CX3CR1, ECM	GM-CSF, IFN-γ, TNF-α, IL-3, perforin and granzyme	T cells, DCs, macrophages	NK cell toxicity is blocked by MDSCs and Treg cells via TGF-β and inhibitory signals	(73–80)
MCs	FcepsilonRI, TLRs, complement receptors, MMPs and adenosine receptor	IL-13, IL-17 and histamine	MDSCs, Tregs, PSCs, CAFs and NK cells	Promoting the proliferation of CAFs, PSCs and M2-TAMs; Mobilizing MDSCs and Tregs infiltration; Reducing the ligands of NK cell receptor	(81–86)