ABSTRACT
Blockade of the programmed cell death 1(PD-1)/PD-1 ligand-1(PD-L1) pathway has been exploited therapeutically in many cancer types. Upregulation of PD-L1 in tumor cells contributes to malignancy through suppression of the T cell-mediated antitumor response. Pyruvate dehydrogenase kinase 1 (PDK1), a glycolytic gate-keeping enzyme, is also known to promote tumor development. Here, we have uncovered a mechanism of regulation of PD-L1 by PDK1 through activation of c-Jun-NH2-kinase (JNK)-c-Jun in ovarian cancer cells. Elevated PDK1 expression was correlated with that of PD-L1 in the TCGA ovarian cancer dataset and ovarian cancer tissue array. Overexpression of PDK1 in ovarian cancer cells impaired CD8+ T cell function by suppressing IFN-γ secretion through the PD-1/PD-L1 pathway. Conversely, knockdown of PDK1 in ovarian cancer cells relieved suppression of CD8+ T cell function. CD8+ T cell apoptosis induced by binding of PD-1 with PD-L1 was increased after co-culture with ovarian cancer cells overexpressing PDK1, while depletion of PDK1 exerted the opposite effect. In vivo experiments revealed synergistic improved overall survival and enhanced inhibition of tumor growth upon co-treatment with dichloroacetate (DCA), a PDK inhibitor, and PD-L1 antibody, accompanied by increased IFN-γ secretion by monocytes infiltrating tumor islets. Moreover, PDK1 expression and CD8+ T cell infiltration were inversely correlated in the ovarian cancer tissue array. Our collective findings provide a novel explanation of how PDK1 contributes to upregulation of PD-L1 in ovarian cancer and highlight its potential as a target therapeutic molecule that cooperates with the immune checkpoint blockade.
ABSTRACT
Based on the data of the field investigation and laboratory and the database of the 8th national forestry inventory, ecosystem carbon density, storage amount, and sequestration potential of tree layer were estimated for five typical plantation ecosystems (Robinia pseudoacacia, Populus spp., Pinus tabuliformis Pinus armandii, which were grouped as one kind of ecosystems, Larix principis-rupprechtii, and Picea asperata) in Gansu Province. The results showed that the average carbon density and total carbon storage of the five typical plantation ecosystems were 139.65 t·hm-2 and 85.78 Tg, respectively. Ecosystem carbon density varied among ecosystems. It followed the sequence of premature (250.70 t·hm-2) > mature (175.97 t·hm-2) > middle-aged (156.92 t·hm-2) > young (117.56 t·hm-2) forest. Meanwhile, carbon storage in these plantations ranked in the order of young (45.47 Tg) > middle-aged (19.54 Tg) > mature (11.84 Tg) > pre-mature (8.93 Tg) forest. Specifically, young and middle-aged plantations contributed the most and accounted for 75.9% of the total carbon storage. The realistic carbon sequestration potential (CPr) by tree layer of the five typical plantation ecosystems in Gansu Province was estimated as 7.27 Tg. The two largest contributors toCPr were R. pseudoacacia (2.49 Tg) and Populus spp. (2.10 Tg). Young plantations (3.78 Tg) showed the largest CPr, followed by middle-aged plantations (2.04 Tg), and the value of premature plantations (0.45 Tg) was the smallest. The maximum carbon sequestration potential (CPmax) might be up to 27.55 Tg, the CPmax with different plantations ranked in the order of R. pseudoacacia (9.42 Tg)> L. principis-rupprechtii (6.22 Tg) ≈ P. asperata (6.36 Tg) > Populus spp. (3.18 Tg) >P. tabuliformis P. armandii (2.37 Tg). The CPmax of young and middle-aged plantations was estimated as 18.48 and 6.89 Tg, respectively, which accounted for 92% of the total maximum carbon sequestration potential.
