Immunomodulatory and anticancer effects of intra-tumoral co-delivery of synthetic lipid A adjuvant and STAT3 inhibitor, JSI-124.
The efficiency of cancer immunotherapy strategies is hampered by the existence of an intra-tumoral immunosuppressive environment involving tolerogenic dendritic cells (DCs) and regulatory T (T(reg)) cells. Hyperactivation of STAT3 in tumor is implicated in the generation of this immunosuppressive environment. The purpose of this study was to test whether simultaneous inhibition of STAT3 in tumor and TLR4 ligand-induced activation of DCs can modulate tumor-induced immunosuppression. For this purpose, the effects of a TLR4 ligand, 7-acyl lipid A, delivered by poly(lactic-co-glycolic acid) nanoparticles (PLGA-NPs) to DCs on the activity of DCs and T(reg) cells was evaluated in vitro. In addition the immunomodulatory and anticancer effects of 7-acyl lipid A PLGA-NPs in combination with a STAT3 inhibitory agent, JSI-124, in a B16 mouse melanoma model was explored, in vivo. PLGA-NP delivery of 7-acyl lipid A to DCs reduced the suppressive effects of T(reg) cells on T cells in vitro. Besides, daily Intra-tumoral co-administration of 7-acyl lipid A PLGA-NPs and JSI-124 in C57BL/6 mice bearing B16-F10 tumor for 8 days resulted in a significant increase in the percentage of tumor infiltrated T cells as compared with control group that received PBS and monotherapy groups. The average tumor volume in the tumor-bearing mice that received JSI-124 plus 7-acyl lipid A PLGA-NPs combination therapy was found to be significantly lower than that in PBS and monotherapy groups. Our findings show a potential for the combination of STAT3 inhibition in tumor and TLR4 induced DC activation in increasing the efficacy of cancer immunotherapy.
Molavi
Ommoleila
O
Faculty of Pharmacy and Pharmaceutical Sciences, University of Alberta, Edmonton, Alberta, Canada.
Ma
Zengshuan
Z
Hamdy
Samar
S
Lavasanifar
Afsaneh
A
Samuel
John
J
D000276:Adjuvants, Immunologic / Q000008:administration & dosage*; D000818:Animals; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000008:administration & dosage*; D003713:Dendritic Cells / Q000187:drug effects / Q000276:immunology; D016503:Drug Delivery Systems; D006016:Glycolates / Q000008:administration & dosage; D007108:Immune Tolerance / Q000187:drug effects* / Q000276:immunology; D015552:Injections, Intralesional; D019344:Lactic Acid; D008050:Lipid A / Q000008:administration & dosage / Q000031:analogs & derivatives*; D008297:Male; D008546:Melanoma, Experimental / Q000188:drug therapy*; D051379:Mice; D008810:Mice, Inbred C57BL; D053758:Nanoparticles / Q000008:administration & dosage; D011100:Polyglycolic Acid; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D050796:STAT3 Transcription Factor / Q000037:antagonists & inhibitors*; D050378:T-Lymphocytes, Regulatory / Q000187:drug effects / Q000276:immunology; D014315:Triterpenes / Q000008:administration & dosage*
D000276:Adjuvants, Immunologic; D006016:Glycolates; D008050:Lipid A; D050796:STAT3 Transcription Factor; C494087:Stat3 protein, mouse; D014315:Triterpenes; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; C038106:cucurbitacin I