Figure 12.

The impact of PSC and tumor cells on immune cells in the pancreatic cancer stroma. (A) NK cells in the stroma display reduced activity. This is mainly due to MDSC and Treg that by TGFβ delivery affect TNFα and IFNγ secretion and SMAD3/4 activation, which inhibit GzmB and perforin transcription. The activating NKG2D receptor become deviated toward PSC due to higher expression of MICAB, where MICAB in tumor cells can become shed by ADAM17, free MICAB fragments further deviating NK cells from attacking the tumor cell. The activating receptors NKp46 and NKp30 become downregulated due to a metabolic shift induced by tumor cell derived LDHA and lactate. Activating receptor can also become occupied by inhibitory receptor, like TIGIT. Finally, tumor cells deliver an IgG like molecule, Ighg1, occupying the FcγR of NK cells and thereby interfering with ADCC. (B) PSC have a strong impact on driving Mϕ into TAM by the delivery of IL4, IL10, IL13, mCSF, and glucocorticoids. TAM deliver IL6 and soluble IL6 receptor binding to gp130 on tumor cells, which activates the JAK/Stat3 pathway promoting tumor cell survival and expansion by cyclin, PCNA Bcl2, and Mcl1 expression. TAM also affect the activity of additional immune cells. Lytic NK cell activity becomes inhibited by TGFβ and IP10. A shift of Th1 to Th2 is supported by TGFβ, IL10, CCL22, and Gal1. Expansion and activity of Treg is assisted by TGFβ, IP10, and CCL11. Finally, CTL recruitment, activation and lytic activity are impaired by TAM-derived TGFβ, IL10, IP10, IDO, and Gal1. (C) A central role of TGFβ in immune deviations relies on binding to the TGFβRII, which promotes RAS, PI3K, and TRAF6/4 pathway activation and on TGFβR1 binding, where phosphorylated Smad4 forms a complex with Smad2/3, the complex migrating into the nucleus promoting together with additional coactivators and transcription factor besides other transcription of NOS, PAI-1 and PDGF. (D) CTL activation is prohibited by tumor cells, PSC and immunosuppressive MDSC, Treg and TAM. The major inhibitory factors and membrane molecules are listed. PSC particularly contribute via POSTN, GAL1, SERPINE2, PGE2, and TLR9. Low level MHCI expression on tumor cells hampers CTL activation, high FASL expression contributes to CTL lysis and IDO and PDL1 are inhibitory receptors. As shown in the overview diagram, preventing CTL activation is the result of coordinated activities between all contributing components. Full name of proteins are listed in Table S1. The dense stroma and poor angiogenesis may hamper leukocyte recruitment. However, there is no paucity of immunosuppressive leukocyte, such that changes in metabolism and activation of signaling cascades are dominating immunosuppression. Feedback circles between all contributing elements create a self-replenishing vicious circle.