P-MAPA immunotherapy potentiates the effect of cisplatin on serous ovarian carcinoma through targeting TLR4 signaling

Abstract

BackgroundToll-like receptors (TLRs) are transmembrane proteins expressed on the surface of ovarian cancer (OC) and immune cells. Identifying the specific roles of the TLR-mediated signaling pathways in OC cells is important to guide new treatments. Because immunotherapies have emerged as the adjuvant treatment for patients with OC, we investigated the effect of a promising immunotherapeutic strategy based on protein aggregate magnesium-ammonium phospholinoleate-palmitoleate anhydride (P-MAPA) combined with cisplatin (CIS) on the TLR2 and TLR4 signaling pathways via myeloid differentiation factor 88 (MyD88) and TLR-associated activator of interferon (TRIF) in an in vivo model of OC.MethodsTumors were chemically induced by a single injection of 100 μg of 7,12-dimethylbenz(a)anthracene (DMBA) directly under the left ovarian bursa in Fischer 344 rats. After the rats developed serous papillary OC, they were given P-MAPA, CIS or the combination P-MAPA+CIS as therapies. To understand the effects of the treatments, we assessed the tumor size, histopathology, and the TLR2- and TLR4-mediated inflammatory responses.ResultsAlthough CIS therapy was more effective than P-MAPA in reducing the tumor size, P-MAPA immunotherapy significantly increased the expressions of TLR2 and TLR4. More importantly, the combination of P-MAPA with CIS showed a greater survival rate compared to CIS alone, and exhibited a significant reduction in tumor volume compared to P-MAPA alone. The combination therapy also promoted the increase in the levels of the following OC-related proteins: TLR4, MyD88, TRIF, inhibitor of phosphorylated NF-kB alpha (p-IkBα), and nuclear factor kappa B (NF-kB p65) in both cytoplasmic and nuclear sites. While P-MAPA had no apparent effect on tumor necrosis factor alpha (TNF-α) and interleukin (IL)-6, it seems to increase interferon-γ (IFN-γ), which may induce the Thelper (Th1)-mediated immune response.ConclusionCollectively, our results suggest that P-MAPA immunotherapy combined with cisplatin could be considered an important therapeutic strategy against OC cells based on signaling pathways activated by TLR4.

NF-κB Signaling in Ovarian Cancer

“…Targeting TLR4 has been investigated as a therapeutic approach to sensitize OC cells to chemotherapy, inhibit migration and invasion and reduce NF-κB activity in OC cells [91,92]. Alternatively, stimulating TLR2 and TLR4 signaling can promote an anti-tumor immune response in OC models in combination with platinum therapy [93]. For example, a protein aggregate compound magnesium–ammonium phospholinoleate–palmitoleate anhydride (P-MAPA) was able to stimulate NF-κB activity in OC tissues, as assessed by p65 nuclear translocation, and increased TLR2 and TLR4 expression [93].…”

<p>miR-34c Targets MET to Improve the Anti-Tumor Effect of Cisplatin on Ovarian Cancer</p>

“…28,29 Strategies are required to sensitize ovarian cancer cells to cisplatin treatment. 30,31 Recent studies have demonstrated that cisplatin resistance is usually accompanied with dysregulation of miRNAs in cancers including ovarian cancer. 13,32,33 MiR-34c, which has been reported to act as a tumor suppressor in hepatocellular carcinoma and breast cancer, 34,35 improves the sensitivity of osteosarcoma to cisplatin.…”

Immunotherapies based on PD-1/PD-L1 pathway inhibitors in ovarian cancer treatment

“…Consequently, it is associated with a poor prognosis for OC patients . TLR‐4 is a factor enabling cancer cells to evade anti‐tumoral response and stimulate tumor progression by inducing local inflammation in TME and increased PD‐L1 expression Immunotherapies targeted against TLRs direct immune response to cancer cells and enhance elimination thereof via apoptosis and autophagy. TLRs, including TLR‐4 and TLR‐2, seem to be crucial in OC pathogenesis.…”

“…Thus, ongoing trials focus on finding factors that could block their activities, including the TLR agonist. The compounds, single or combined, are potentially effective tools in OC treatment . TLR agonists were tested in clinical trials in patients with solid tumors, including OC, and found only mild adverse effects .…”