Immunomodulatory and anticancer effects of intra-tumoral co-delivery of synthetic lipid A adjuvant and STAT3 inhibitor, JSI-124

Abstract

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.

Keywords::

• JSI-124
• 7-acyl lipid A
• STAT3
• tumor immunosuppression

Acknowledgment

This work was supported by research grants from Canadian Institute of Health Research (CIHR, grant MOP 42407) and the National Science and Engineering Research Council (NSERC, grants G121210926 and G121220086). Ommoleila Molavi was supported by Rx and D HRF/CIHR graduate student research scholarship and a scholarship from the Iranian Ministry of Health and Medical Education. Authors thank Biomira (Oncothyreon) Inc. for the generous gift of 7-acyl lipid A compound.

Declaration of interest: The authors report no financial conflicts of interest. The authors alone are responsible for the content and writing of this paper.