Drug Target for Cancer: PD-L1

Drug Targets for Cancer: PD-L1 and Cancer

As an immune suppression mechanism, the expression of PD-L1 is elevated in many types of cancer and is often correlated with poor patient prognosis and predictive of responses to Abs against PD-1/PD-L1. Nevertheless, tumours that do not express detectable levels of PD-L1 on the cell surface can also respond to Abs against PD-1, suggesting that the predictive value of PD-L1 expression may not be uniformly applicable to all types of cancer. On the other hand, this may be associated with unresolved technical and biological issues that preclude an accurate detection of PD-L1 with a standardised criterion for quantitation of PD-L1 expression in clinical samples. Moreover, it is well recognised that there are wide intra- and intertumoural variations in the expression of PD-L1, which indicates that sampling of cancer tissues may also impinge on the outcome of PD-L1 detection. Regardless, there is increasing evidence showing that the expression of PD-L1 in cancer cells is mediated by oncogenic activation of signalling pathways and is also regulated by factors in the tumour microenvironment. In metastatic melanoma, both PD-L1 and tumour infiltrating immune (mononuclear) cells (TIMC) are associated with prognosis. While expression of TIMC without PD-L1 leads to beneficial treatment outcome, expression of both TIMC and PD-L1 has no such advantage, indicating that PD-L1 is negatively associated with prognosis. Under the absence of TIMC, expression of PD-L1 does not affect prognosis. Expression of PD-L1 is associated with poor prognosis in many cancers. For example, in melanoma, PD-L1 could be a marker that defines a subset of melanoma with distinct genetic and morpho-phenotypic features, increased aggressiveness and invasiveness. PD-L1 affects cancer treatment outcomes through various mechanisms. PD-L1 in ovarian cancer cells inhibited CTL function and promoted cancer cell dissemination. PD-L1 may be involved in cell proliferation and progression, which could also be a factor leading to poor prognosis. It has been demonstrated that PD-L1 up-regulation due to decreased miR-200 results in dysfunction of CD8 T-cells, which coupled with epithelial-mesenchymal transition (EMT) to increase metastasis. PD-L1 and EMT can regulate each other to form feed-forward regulation. Expression of PDL1 is associated with drug resistance to anti-cancer therapy such as BRAF inhibitor resistance in metastatic melanoma patients. This could be caused by both PD-L1-induced immune inhibition and PD-L1-promoting cell proliferation.

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Drug Targets for Cancer: PD-L1 Related Reference

Chen J, Jiang C C, Jin L, et al. Regulation of PD-L1: A novel role of pro-survival signalling in cancer[J]. Annals of Oncology, 2015: mdv615.

Drug Targets for Cancer: PD-L1 Related Information