The mechanism of ABL1 upregulating the expression of PD-L1 and the therapeutic effect of PD-L1 and STAT3 inhibitors in lung adenocarcinoma

Dongfang Tang, Haoyao Jiang, Zhigang Li,  Wen Gao,  Yifeng Sun

Abstract:

The upregulation of programmed cell death-ligand 1 (PD-L1) and continuous mutation of EGFR could induce chemoresistance in somatic cancers, however, the molecular mechanism of oncogene ABL1 in regulating the expression of PD-L1 in lung adenocarcinoma (LAD) remains unclear. In addition, the therapeutic effect of STAT3 and PD-L1 inhibitors in LAD is not fully understood. The ABL1 lentiviruses were used to transfect LAD cell lines (H1975, PC-9) with different EGFR mutation subtypes. Next, the expression of the JAK/STAT3 and PD-L1 pathway was detected followed by the treatment with STAT3 and PD-L1 inhibitors. Lastly, we observed the apoptosis and expression of STAT3 and PD-L1 before and after treatments in transfected and knocked down cell lines. The expression of ABL1 was upregulated by more than 3.71-fold and the expression of PD-L1 increased by 4.85-fold in lung cancer tissues compared with para-cancer tissues (both p<0.01), the ABL1 could induce upregulation of PD-L1 in LAD cell lines. Furthermore, the STAT3 inhibitor might induce more apoptosis than the PD-L1 inhibitor in both H1975 and PC-9 cell lines (both p<0.01) The STAT3 inhibitor combined with PD-L1 inhibitor had a synergistic effect on the PC-9 cell line, and the antagonistic effect was observed on the H1975 cell line. Furthermore, the expression of PD-L1 decreased almost equally after the PD-L1 inhibitor combined with a STAT3 inhibitor, or the STAT3 inhibitor alone (p>0.05). In addition, the STAT3 and PD-L1 decreased significantly after the STAT3 inhibitor compared with other treatments on the H1975 cell line (both p<0.01). To conclude, the EGFR mutation subtypes might influence the therapeutic efficacy in the treatment with PD-L1 inhibitor combined with STAT3 inhibitor on LAD cell lines.