HIF1α 依赖性与非依赖性通路调控前列腺癌中 PD-L1 的表达

PD-L1/PD-1 pathway is a major pathway exploited by human cancer types, which is a target for current immunotherapy.

We investigated tumor microenvironmental factors involved in PD-L1 induction in prostate cancer (PC).

We studied the expression of PD-L1 in a series of 66 PCs, in parallel with the expression of hypoxia- and acidity-related immunohistochemical markers (Hypoxia-inducible factor HIF1 , and lactate dehydrogenase LDHA) and tumor-infiltrating lymphocyte TIL density. Experiments with three PC cell lines, the 22Rv1, DU145, and PC3 were conducted focusing on the inducibility of PD-L1 by hypoxia, acidity, lymphocyte interactions, and radiation. In tissues, PD-L1 expression by cancer cells was directly related to PD-L1 expression by TILs and macrophages (p < 0. 05), and the overexpression of HIF1 and LDH5 (p < 0. 05).

TIL density was inversely related to F1 (p = 0. 02). Exposure of PC cell lines to hypoxia strongly induced PD-L1 and protein and mRNA levels, directly controlled by HIF1 function (p < 0. 001). Irradiation with 20 Gy had no apparent effect on PD-L1 expression.

Culturing PC cell lines with culture medium (CM) from PBMCs strongly induced PD-L1 at protein and mRNA levels, independently from HIF1 , which was also confirmed when cells were incubated with Interferon- (p < 0. 001). It is concluded that the combination of anti-PD-L1/PD-1 immunotherapy with hypoxia/HIF-targeting may be important in the treatment of specific subgroups of PC patients.