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.

Materials for Immunotherapy

“…Huang and co‐workers developed cationic liposome‐protamine‐HA nanoparticles to deliver siRNA to silence CD47 expression in solid tumors . Starting in 2017, the Huang group published a series of papers using a similar particle design (i.e., a liposome‐protamine‐DNA (LPD) nanoparticle) to deliver genes for various anticancer purposes, including those that encode for proteins that bind to (or trap): i) the immunosuppressive proteins PD‐L1 and C‐X‐C motif chemokine (CXCL)12, ii) the signaling protein Wnt family member 5A (Wnt5a), which has been implicated in inducing dendritic cell tolerance, iii) IL‐10, which is known to suppress dendritic cells from releasing IL‐12, to develop Th1 responses, iv) LPS, which relieved the immunosuppressive microenvironment and boosted anti‐PD‐L1 therapy against colorectal tumors, and v) CCR‐7, which is associated with the metastasis of breast cancer . The group also investigated the delivery of siRNA to silence high mobility group protein A1 (HMGA1), which is associated with immunosuppression .…”

Nonlinear Supramolecular Polymers for Therapeutic Applications

“…Chemotherapy drug delivery systems were also developed for breast cancer therapy. Yan presented a concise and efficient drug‐loading system by the strategy that Fe(III) ions triggered coordination cross‐links of tannic acid (TA) molecules coating the drug cores ( Figure A). In this method, TA without toxic and water‐soluble properties can coordinate with Fe(III) cross‐linked complex and bind to the internal PTX via hydrogen bond at the same time.…”

“…C) Volumes, weights, and images of MCF‐7 tumor. Reproduced with permission . Copyright 2016, American Chemical Society.…”

Tumor neoantigen heterogeneity impacts bystander immune inhibition of pancreatic cancer growth

“…We selected candidate binders based on %Rank rather than nM Affinity, following the recommendation of the server developers. We generated a cell line from the genetically engineered KPC mice model [19][20][21] with KRAS G12D and p53 R172H oncogenic driver mutations, and inoculated cells orthotopically in mice sharing the same genetic background, for two reasons: Firstly, having a non-spontaneous model allowed us to precisely control the frequency of neoantigen to assay the subsequent effect on tumor elimination while reasonably replicating the desmoplastic and immunosuppressive characters of the GEMM tumors. Secondly, it allowed us to engineer the cell line to express luciferase and quantitatively monitor tumor growth by bioluminescence imaging.…”

“…We tested the effects on tumor growth and immunity in orthotopic animal models. We used nanoparticle-based drug delivery to locally and transiently express immunomodulatory cytokines in the PDAC tumors 20,21 , and as a tool to probe the effect of TME alterations on bystander killing. A simplified scheme of the approach is presented in Fig.…”