The PD-L1–mTOR intersection in tumor migration and invasion

Programmed death-ligand 1 (PD-L1) has emerged as an important player in intrinsic tumor cell biology besides its canonical immune checkpoint function. Cumulative experimental data points to a role for PD-L1 in promoting and maintaining an invasive cell phenotype within different cancer cells through its interaction with mechanistic target of rapamycin (mTOR) signaling. In this review, we summarize the main experimental data pointing to the PD-L1/mTOR interaction in tumor cell invasion capacity both in vitro and in vivo. In this crosstalk, PD-L1 expression is induced by IFN-γ/STAT1 and IL-6/STAT3 pathways, as well as mTOR activity by its upstream effectors like EGFR and other tyrosine kinase receptor ligands. Interestingly, PD-L1 itself seems to play a role in mTOR activation. In many of these models, the PD-L1 importance in cell migration capacity is evidenced by two major observations: (1) its knockout impairs cell invasion capacity and, (2) its upregulation is associated with increased cell migration and both the induction and maintenance of epithelial-mesenchymal transition (EMT) phenotype markers, such as increased N-cadherin and ZEB1 and decreased E-cadherin. We also summarize the main clinical trials combining mTOR pathway inhibitors with anti-PD-L1 antibodies in different cancer types.