In conclusion, our data support a regulatory mechanism of PD-L1 expression on tumor cells and immune suppression via miR-148a-3p downregulation in colorectal cancer.
Deciphering the molecular mechanisms highlighted the TGIF1 loss-induced activation of the hyaluronan synthase 2 (HAS2)-CD44 signaling pathway and upregulation of the immune checkpoint regulator PD-L1 to facilitate the epithelial-mesenchymal transition (EMT) and tumor immune suppression.
SIGNIFICANCE: These findings identify PD-L1 as a critical component of UV-induced immune suppression in the skin, which facilitates immunoevasion of oncogenic melanocytes and development of melanoma.<i>See related commentary by Sahu, p. 2805</i>.
Further, the ability of scFv PD-L1 to rescue PD-1/PD-L1 mediated immune suppression was demonstrated in a co-culture system consisting of human-derived immune cells and further demonstrated in several syngeneic mouse models including an intracranial tumor model.
The programmed cell death 1 (PD-1)/programmed cell death ligand 1 (PD-L1) axis plays an important role in controlling immune suppression by down-regulating T effector cell activities, enabling tumor cells to escape from the host's antitumor immunsurveillance.
PTEN immunohistochemical loss, a common event in endometrioid-type endometrial carcinoma and associated with local immune suppression in melanoma, was not associated with PD-L1 expression or lymphocyte/macrophage infiltration of the tumor.
In vivo experiments further revealed that the triggered immune response can be synergistically promoted by IDO inhibition and PD-L1 blockade; the responses included the enhancement of tumor-infiltrating lymphocytes, including CD45<sup>+</sup> leukocytes, CD4<sup>+</sup> T cells, CD8<sup>+</sup> T cells, and NK cells; the inhibition of the immune suppression activity of regulator T cells (T<sub>regs</sub>); and the production of INF-γ.
Hence, we further developed soluble programmed death receptor-1 (sPD1)-expressing senescent cells to overcome PD-L1/PD-1-mediated immune suppression while vaccinating to promote dendritic cell (DC) maturity, thereby amplifying T-cell activation.
The programmed death-ligand 1 (PD-L1) expression by tumors results in potent antitumor immune suppression through binding to programmed death-1 (PD-1) on T cells and subsequent inhibition of T cells activity.
However, recent studies have shown that STAT3 activation leads to upregulation of program death receptor-ligand 1 (PD-L1, an immune checkpoint protein that plays a major role behind evasion of immune systems by growing tumors) expression levels in tumor cells, leading to enhanced immune suppression.
Our findings indicate that Klf1 and Egr2 are modulators of PD-L1-mediated immune suppression in CD4<sup>+</sup> T cells and might provide new insights into therapeutic targets for autoimmune diseases and malignancies.
While both tumor- and host-derived PD-L1 can play critical roles in immune suppression, differences in tumor immunogenicity appear to underlie their relative importance.
Our previous <i>in vitro</i> cellular studies with human and mouse PD-L1<sup>+</sup> tumor cells demonstrated that a soluble form of the costimulatory molecule CD80 prevented PD-L1-mediated immune suppression and restored T-cell activation by binding PD-L1 and blocking interaction with PD-1.
PD-L1 expression in both the host and tumour compartment contribute to immune suppression in a non-redundant fashion, suggesting that both sources could be predictive of sensitivity to therapeutic agents targeting the PD-L1/PD-1 axis.