Abstract
Programmed cell death ligand 1 (PD‑L1) expressed in cancer cells interacting with its receptor programmed cell death 1 (PD‑1) expressed in immune cells represents a regulatory axis linked to the suppression and evasion of host immune functions. The blockade of PD‑1/PD‑L1 interaction using monoclonal antibodies has emerged as an effective therapy for several solid tumors; however, durable response has been observed in a subset of patients with PD‑L1-positive tumors. Thus, the understanding of the mechanisms responsible for the expression of PD‑L1 in tumor cells may help to improve the response to PD‑L1 blockade therapies. In this study, we investigated whether resveratrol, a grape-derived stilbenoid with immunoregulatory activity, modulates the expression of PD‑L1 in breast and colorectal cancer cells. The surface expression of PD‑L1 was determined by flow cytometry in cancer cells treated with resveratrol and/or piceatannol. Each stilbenoid alone induced PD‑L1 and when used in combination, elicited a synergistic upregulation of PD‑L1 in some cell lines. The induction of PD‑L1 by the combined use of stilbenoids was most pronounced in the Cal51 triple-negative breast cancer (TNBC) and SW620 colon cancer cells. The observed induction of PD‑L1 was transcriptionally mediated by nuclear factor (NF)-κB, as shown by NF‑κB reporter assays, the nuclear accumulation of the p65 subunit of NF‑κB, inhibition by the IKK inhibitor, BMS‑345541, and histone the modification inhibitors, resminostat, entinostat or anacardic acid. Combined treatment with resveratrol and piceatannol also decreased tumor cell survival as indicated by the upregulation of the DNA damaging marker, γH2AX, the cleavage of caspase 3, the downregulation of the survival markers, p38-MAPK/c‑Myc, and G1-to-S cell cycle arrest.