01/18/2018

Journal of Ovarian Research (2018) 11:8

JOURNAL OF OVARIAN RESEARCH

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

Abstract

Background: Toll-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 toguide 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 magnesiumammoniumphospholinoleate-palmitoleate anhydride (P-MAPA) combined with cisplatin (CIS) on the TLR2 and TLR4signaling pathways via myeloid differentiation factor 88 (MyD88) and TLR-associated activator of interferon (TRIF) inan in vivo model of OC.

Methods: Tumors 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, theywere 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.

Results: Although 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 ofP-MAPA with CIS showed a greater survival rate compared to CIS alone, and exhibited a significant reduction intumor volume compared to P-MAPA alone. The combination therapy also promoted the increase in the levels ofthe following OC-related proteins: TLR4, MyD88, TRIF, inhibitor of phosphorylated NF-kB alpha (p-IkBα), and nuclearfactor kappa B (NF-kB p65) in both cytoplasmic and nuclear sites. While P-MAPA had no apparent effect on tumornecrosis factor alpha (TNF-α) and interleukin (IL)-6, it seems to increase interferon-γ (IFN-γ), which may induce theThelper (Th1)-mediated immune response.

Conclusion: Collectively, our results suggest that P-MAPA immunotherapy combined with cisplatin could beconsidered an important therapeutic strategy against OC cells based on signaling pathways activated by TLR4.Keywords: Ovarian cancer, P-MAPA, Cisplatin, TLR2, TLR4, NF-kB 

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