Table 1. Immune-based mechanisms of targeted therapy.
| Pathway inhibition | Immune Potentiating Effects | Refs |
|---|---|---|
| PI3K/AKT/mTOR pathway | ||
| PI3K inhibition | Heighten the antitumor properties of TLR ligands Increase accumulation of effector T cells Dampen Treg function Inhibit myeloid cells Inhibit immunosuppressive TAMs |
[7] [7] [8] [8] [8] |
| AKT inhibition | Sensitize tumor cells to immune destruction by disrupting Mcl-1 mediated anti-apoptotic signaling | [10,11] |
| mTOR inhibition | Generate memory CD8 + T cells Reduce Tregs |
[13–16] [13–16] |
| MAPK pathway | ||
| BRAF inhibition | Directly enhance T cell function Increase antigen expression Increase MHC class I expression Restore IL-12 and TNF-α production by DCs Restore CD80, CD83, and CD86 expression on DC Reduce MDSCs Reduce the expression of VEGF Suppress the expression of IL-1 Increase CD8 T cell and NK cells |
[31] [33–35] [36] [37] [37] [38] [39] [40] [41] |
| MEK inhibition | Protect effector CD8 T cells from death caused by chronic T cell receptor stimulation Increase antigen expression Restore IL-12 and TNF-α production by DCs |
[32] [34] [37] |
| VEGF pathway | ||
| VEGF/VEGFR inhibition | Increase extravasation of T cell Augment DC maturation and function |
[65, 66] [59, 60] |
| Multikinase inhibition | Decrease the number and function of MDSCs and Tregs Increase cytotoxic lymphocyte infiltration and response Enhance IFN-gamma production Diminish expression of CTLA4, PD1, and PDL-1 |
[69–71] [69–71] [69–71] [69–71] |
| C-kit pathway | ||
| C-kit inhibition | Facilitate production of Th1 cytokine Prompt NK cell activation Suppress IDO production Inhibit Treg and MDSCs |
[84, 85, 90] [86, 87] [89] [88–90] |
| Epigenetic pathway | ||
| Epigenetic inhibition | Increase tumor antigen expression Increase MHC molecules expression Induce the expression of NKG2DL (MICA/B) Reduce Treg cells and MDSCs |
[109–111] [109–111] [112, 113] [114, 115] |
| Others | ||
| Proteasome inhibition | Decrease expression of peptide–MHC class I complex (thereby sensitizing tumor to NK cells) Increase expression of FAS and the TRAIL receptor DR5 Induce NOXA-mediated enhancement of mitochondrial SMAC release (thereby increasing sensitivity to T cells) |
[130] [131] [132] |
| HSP90 inhibition | Increase tumor antigen presentation Augment the expression of NKG2DL (MICA/B) |
[135, 136] [137, 138] |
Abbreviations: TAMs, tumor-associated macrophages; TLR, toll-like receptor; Mcl-1, myeloid cell leukemia-1; Treg, regulatory T cell; MHC, major histocompatibility complex; IL, Interleukin; TNF--α, tumor necrosis factor-α; DCs, dendritic cells; NK, natural killer; MDSCs, myeloid-derived suppressor cells; CTLA-4, cytotoxic T-lymphocyte-associated protein 4; PD-1, programmed death 1; PD-L1, programmed death-ligand 1; Th1, T helper 1; IDO, indoleamine 2, 3-dioxygenase; NKG2DL, natural killer group 2, member D ligands; MICA/B, major histocompatibility complex class I related-A and –B; TRAIL, TNF-related apoptosis-inducing ligand.