Interleukin-27 Gene Delivery for Modifying Malignant Interactions Between Prostate Tumor and Bone

Abstract

We have examined the role of a novel cytokine, interleukin-27 (IL-27), in mediating interactions between prostate cancer and bone. IL-27 is the most recently characterized member of the family of heterodimeric IL-12-related cytokines and has shown promise in halting tumor growth and mediating tumor regression in several cancer models, including prostate cancer. Prostate cancer is frequently associated with metastases to the bone, where the tumor induces a vicious cycle of communication with osteoblasts and osteoclasts to induce bone lesions, which are a significant cause of pain and skeletal-related events for patients, including a high fracture risk. We describe our findings in the effects of IL-27 gene delivery on prostate cancer cells, osteoblasts, and osteoclasts at different stages of differentiation. We applied the IL-27 gene delivery protocol in vivo utilizing sonoporation (sonodelivery) with the goal of treating and reducing the growth of prostate cancer at a bone metastatic site in vivo. We used a new model of immune-competent prostate adenocarcinoma and characterized the tumor growth reduction, gene expression, and effector cellular profiles. Our results suggest that IL-27 can be effective in reducing tumor growth, can help normalize bone structure, and can promote enhanced accumulation of effector cells in prostate tumors. These results are promising, because they are relevant to developing a novel IL-27-based strategy that can treat both the tumor and the bone, by using this simple and effective sonodelivery method for treating prostate tumor bone metastases.

Frontline Science: Human bone cells as a source of IL-27 under inflammatory conditions: role of TLRs and cytokines

“…Scale bar = 50 mM. associated with both reduction of tumor growth and limitation of bone destruction [52], suggesting that IL-27 may be of therapeutic interest to limit bone metastases. Interestingly, type I IFNs, which have a major role in IL-27 induction in osteoblasts, have been associated with reduced bone metastasis and prolonged survival in mouse and human studies [53].…”

Human adipose-derived mesenchymal stromal cell pigment epithelium–derived factor cytotherapy modifies genetic and epigenetic profiles of prostate cancer cells

“…A better understanding of the linkage between genetic and epigenetic events in tumor growth probably will result in a more effective use of ASC or ASC-PEDF for treating prostate cancer. We anticipate that delivery of immunostimulatory cytokines (36), anti-angiogenic molecules, apoptosis-inducing genes, nanoparticles and/or therapeutic exosomes (37) by ASCs or other stem cells to tumors will comprise very promising approaches for antitumor therapy. Future successful therapies may combine traditional targeted and stem cell—directed gene therapies to enable significant advances in the treatment of prostate and other cancers.…”

The Yin and Yang Aspects of IL-27 in Induction of Cancer-Specific T-Cell Responses and Immunotherapy

“…Recently, IL-27 gene delivery as a single agent for cancer therapy has been tested in animal models with metastatic prostate cancer and shows promising results [83], suggesting that IL-27-based gene therapy has the potential to be used for cancer therapy. Since IL-27 enhances T effector cell survival [11] and systemic IL-27 reduces numbers of Treg cells [13], IL-27-based gene therapy that leads to systemic production of IL-27 in the blood may present a unique opportunity to optimize T-cell-based immunotherapy.…”