Figure 4.

The relationship between metalloproteinases and immune cells. When T-cell receptor (TCR) of T cells interact with the major histocompatibility complex (MHC II) of antigen presenting cells (APCs), co-stimulatory receptor CD40L(CD154) expression is rapidly upregulated and linked to CD40, and subsequently released from the T cell surface by cleavage by ADAM10 and ADAM17. Lymphocyte Activation Gene-3 (LAG-3), T-cell immunoglobulin and mucin domain-containing protein-3 (TIM-3) are T-cell coinhibitory receptors can be cleaved by ADAM10 and ADAM17 yielding soluble form sLAG-3 and sTIM-3. SLAG-3 binds to MHCII inhibiting the activation of T cells and inducing dendritic cell maturation, sTIM-3 can impair the antitumor immune response of T cells. ADAM10 and ADAM17 can both produce different cleavage products of PD-L1, which called soluble PD-L1 (sPD-L1) and shed from the surface of tumor cells, inducing apoptosis of CD8+ T cells and inhibiting antitumor immunity. In B cells, Notch2 heterodimers bind to ligands DLL1 presented on antigen presenting cells (APCs), which initiates ADAM10 resulting in the release of the Notch intracellular domain that translocating to the nucleus to trigger the expression of downstream target genes. The IgG Fc receptor FcγRIII (CD16), recognizing blinding the Fc part of the IgG antibody of tumor cells and dissolving the cells by Ab-dependent cell-mediated cytotoxicity (ADCC), on NK cells can be cleaved by the metalloprotease ADAM17, leading to NK cell dysfunction and reduced ADCC capacity. MMPs and ADAMs can cleave ligands of the activated receptor NKG2D, such as MIC, on the surface of tumor cells, they bind to NKG2D inducing endocytosis this receptor and causing tumors to evade immune surveillance. Tumour-associated macrophages (TAM) can secret MMPs to promote tumor angiogenesis, invasion and regulate immune response. The chemokine CCL2 secreted by MMP11-overexpressing macrophages activates MAPK pathway, including Phosphorylation of ERK1/2 and JNK, through combined with its receptor CCR2, thereby promoting the migration of cancer cells by up-regulating MMP9. MMP11-expressing macrophages can also upregulate PD-L1 expression and induce immunosuppression of cancer cells. MMP2 and MMP9 released by mast cells (MCs) can promote tumor angiogenesis and tumor invasiveness, respectively. MMP2 as a physiological TLR2 ligand can specifically trigger TLR2 and then increase OX40 ligand (OX40L), which interacted with OX40, on dendritic cells (DCs) to drive T cell responses leading to modulation of immune responses.