Regulation of programmed death ligand 1 (PD‐L1) expression by TNF‐related apoptosis‐inducing ligand (TRAIL) in triple‐negative breast cancer cells

Abstract

Triple‐negative breast cancer (TNBC) is an aggressive form of breast cancer that lacks targeted therapies. Previous studies have shown that TNBC cells are highly sensitive to tumor necrosis factor (TNF)‐related apoptosis‐inducing ligand (TRAIL), making it a promising agent for treating TNBC. However, the development of TRAIL resistance limits its further clinical development, and the underlying mechanisms are not fully understood. In this study, we report the role of PD‐L1 in TRAIL resistance. Specifically, we found that TRAIL treatment increases PD‐L1 expression in TRAIL‐sensitive cells and that basal PD‐L1 expression is increased in acquired TRAIL‐resistant cells. Mechanistically, we found that increased PD‐L1 expression was accompanied by increased extracellular signal‐regulated kinase (ERK) activation. Using both genetic and pharmacological approaches, we showed that knockdown of ERK by siRNA or inhibition of ERK activation by the mitogen‐activated protein kinase kinase inhibitor U0126 decreased PD‐L1 expression and increased TRAIL‐induced cell death. Furthermore, we found that knockout or knockdown of PD‐L1 enhances TRAIL‐induced apoptosis, suggesting that PD‐L1‐mediated TRAIL resistance is independent of its ability to evade immune suppression. Therefore, this study identifies a noncanonical mechanism by which PD‐L1 promotes TRAIL resistance, which can be potentially exploited for immune checkpoint therapy.

Immune modulation of innate and adaptive responses restores immune surveillance and establishes anti-tumor immunological memory

“…Fas is a proapoptotic receptor that when expressed renders cancer cells more susceptible to its ligand (FASL), which is also expressed by cancer cells as well as by immune cells (76,77). Tumor necrosis factor (TNF)-related apoptosis-inducing ligand (TRAIL) plays an important role in apoptosis and tumor immunosurveillance (78,79). TRAIL selectively induces apoptosis in cancer cells by binding to DR4 and DR5.…”

The Role of TRAIL in Apoptosis and Immunosurveillance in Cancer

“…In addition to the induction of apoptosis, TRAIL has also been shown to activate several non-apoptotic signaling pathways. Among these pathways are the extracellular signal-regulated kinase (ERK) [55][56][57], AKT [56,58,59] and NF-κB [60][61][62] pathways. These pathways are usually cell-type specific, and the activation of these pathways inhibits apoptosis [55,57,58,61,63,64].…”

“…Among these pathways are the extracellular signal-regulated kinase (ERK) [55][56][57], AKT [56,58,59] and NF-κB [60][61][62] pathways. These pathways are usually cell-type specific, and the activation of these pathways inhibits apoptosis [55,57,58,61,63,64]. For example, a previous study suggests that TRAIL can activate the ERK, AKT, and NF-κB pathways through a secondary complex that forms after the formation of DISC [65].…”

“…Furthermore, TRAIL death receptor 2 is overexpressed in KRAS-mutated tumors, and this overexpression activates the Rac1/PI3K pathway, which in turn promotes KRAS-driven tumor progression, invasion, and metastasis [71]. A recent study showed that TRAIL could induce the expression of the immune checkpoint protein programmed death-ligand 1 (PD-L1) via the ERK pathway, and that inhibiting it made TRAIL-resistant cells susceptible to TRAIL-induced apoptosis [57]. These findings show that the TRAIL pathway can activate oncogenic signaling pathways and immunological checkpoint responses and produce cytokines/chemokines that promote cancer cell survival.…”

Targeting TRAIL Death Receptors in Triple-Negative Breast Cancers: Challenges and Strategies for Cancer Therapy

“…Immune therapies have shown efficacy in TNBC [ 2 , 3 , 4 , 5 , 6 ]. One recent study has shown TRAIL-induced transcriptional upregulation of PD-L1 expression in the MDA-MB-231 TNBC cell line via an ERK-dependent mechanism [ 194 ]. Interestingly, RNAi-mediated knockdown of PD-L1 increased sensitivity to TRAIL agonists in vitro, suggesting a non-immune-mediated mechanism of resistance mediated by PD-L1.…”