Local Blockade of Interleukin 10 and C-X-C Motif Chemokine Ligand 12 with Nano-Delivery Promotes Antitumor Response in Murine Cancers.

Abstract

In many cancers, the tumor microenvironment (TME) is largely immune suppressive, blocking the antitumor immunity and resulting in immunotherapy resistance. Interleukin 10 (IL-10) is a major player controlling the immunosuppressive TME in different murine tumor models. Increased IL-10 production suppresses intratumoral dendritic cell production of interleukin 12, thereby limiting antitumor cytotoxic T-cell responses and activation of NK cells during therapy. We engineered, formulated, and delivered genes encoding an IL-10 protein trap to change immunosuppressive TME, which could enhance antitumor immunity. Additionally, to achieve stronger and long-term therapeutic efficacy in a pancreatic cancer model, we targeted C-X-C motif chemokine ligand 12 (CXCL12), a key factor for inhibiting T-cell tumor infiltration, and simultaneously delivered an IL-10 trap. Following three injections of the lipid-protamine-DNA (LPD) nanoparticles loaded with trap genes (IL-10 trap and CXCL12 trap), we found tumor growth reduction and significantly prolonged survival of the host compared to control groups. Furthermore, the combination trap gene treatment significantly reduced immunosuppressive cells, such as M2 macrophages, MDSCs, and PD-L1⁺ cells, and activated immunosuppressive tolerogenic dendritic cells, NK cells, and macrophages intratumorally. We have also shown that, when effectively delivered to the tumor, the IL-10 trap gene alone can inhibit triple-negative breast cancer growth. This strategy may allow clinicians and researchers to change the immunosuppressive microenvironment in the tumor with either a single therapeutic agent or in combination with other immunotherapies to prime the immune system, preventing cancer invasion and prolonging patient survival.