Table 1.
Evidence of PD-L1 reverse signaling.
| Cell Types | Biological Effects | Experimental Setting | Reference |
|---|---|---|---|
| Mouse ovarian cancer (ID8) melanoma (B16) | PD-L1 down-modulation enhanced autophagy, reduced mTORC1 activity and reduced tumor growth and metastasis | RNA interference | [70] |
| B16 melanoma (CT26 colorectal and 4T1 breast cancer) | PD-L1 signaling protects cancer cells from interferon (IFN) cytotoxicity and accelerates tumor progression | CRISPR-Cas9; mutations in intracellular domains | [71] |
| T cells | Inhibitory interaction between B7-1 (CD80) and PD-L1 that affects T cell activation and cytokine production | Cd28−/−, Ctla4−/−, Cd274−/− cells; in vitro binding assays with Ig fusion proteins | [72] |
| Human esophageal cancer (Eca-109 cell line) | PD-L1 expression promoted cell viability, migration and epithelial to mesenchymal transition (EMT) phenotype | RNA interference and over-expression | [73] |
| Breast cancer (MDA-MB-231 cell line) | PD-L1 expression necessary for expression of OCT-4A, Nanog and the stemness factor, BMI1 in cancer stem cells | PD-L1 knock-down by shRNA and ectopic expression | [75] |
| Classical Hodgkin lymphoma (HL cell lines) | Stimulation of the HL cell lines with PD-L1 antibody increases cell survival and proliferation and reduces apoptosis | In vitro stimulation with agonist PD-L1 Ab | [68] |
| Bone marrow-derived macrophages, tumor-associated macrophages | PD-L1 signal block activates macrophages (CD80, MHC II up-regulation, increased IL-12 and TNF production); PD-L1 signals constitutively inhibit mTOR pathway signaling | In vitro Ab treatment, sPD-1 and sCD80 stimulation; PD-L1 KO macrophages; in vivo effect on tumor growth of B16 melanoma and PyMT breast tumors and macrophage phenotype | [69] |
PD-L1: programmed death ligand 1; TORC1: Target of rapamycin complex 1; CTLA-4: cytototoxic T lymphocyte antigen 4; CRISPR: Clustered Regularly Interspaced Short Palindromic Repeats; OCT-4: octamer-binding transcription factor 4; BMI1: B-cell-specific Moloney murine leukemia virus integration site 1; shRNA: short hairpin RNA; HL: Hodgkin Lymphoma; TNF: tumor necrosis factor; PyMT: polyoma middle T.