Radiation-Induced Amplification of TGFB1-Induced Mesenchymal Stem Cell–Mediated Sodium Iodide Symporter (NIS) Gene 131I Therapy

Abstract

Purpose: The innate tumor homing potential of mesenchymal stem cells (MSCs) has been used for a targeted delivery of the theranostic sodium iodide symporter (NIS) transgene into solid tumors. We have previously shown that external beam radiotherapy (EBRT) results in the enhanced recruitment of NISexpressing MSCs into human hepatocellular carcinoma (HuH7). In parallel, the tumor-associated cytokine TGFB1 becomes strongly upregulated in HuH7 tumors in response to EBRT.Experimental Design: We therefore evaluated the effects of combining focused EBRT (5 Gy) with MSC-mediated systemic delivery of the theranostic NIS transgene under control of a synthetic TGFB1-inducible SMAD-responsive promoter (SMAD-NIS-MSCs) using 123 I-scintigraphy followed by 131 I therapy in CD1 nu/nu mice harboring subcutaneous human hepatocellular carcinoma (HuH7).Results: Following tumor irradiation and SMAD-NIS-MSC application, tumoral iodide uptake monitored in vivo by 123 I-scintigraphy was enhanced as compared with nonirradiated tumors. Combination of EBRT and SMAD-NIS-MSC-mediated 131 I therapy resulted in a significantly improved delay in tumor growth and prolonged survival in therapy mice as compared with the combined therapy using CMV-NIS-MSCs or to control groups receiving EBRT or saline only, or EBRT together with SMAD-NIS-MSCs and saline applications.Conclusions: MSC-based NIS-mediated 131 I therapy after EBRT treatment dramatically enhanced therapeutic efficacy when a TGFB1-inducible SMAD-responsive promoter was used to drive NIS expression in adoptively applied MSCs. The remarkable therapeutic effect seen is thought to be linked in large part to the enhanced TGFB1 produced in this context, which leads to a highly selective and focused amplification of MSC-based NIS expression within the tumor milieu.

The sodium iodide symporter (NIS): novel applications for radionuclide imaging and treatment

“…This is thought to support a self-energizing therapy cycle that is likely responsible for the pronounced therapeutic effect seen. The therapeutic effects went well beyond what was seen in all previous studies by this group using MSCs or polymers as non-viral NIS transgene delivery vehicles (Schug et al 2019b).…”

Mesenchymal Stem Cells‐Based Targeting Delivery System: Therapeutic Promises and Immunomodulation against Tumor

“…[16] Remarkably, a recent study demonstrated considerable advantages of targeted drug delivery using MSCs-TDDSs for non-small-cell lung cancer treatment, and successful eradication of A549 cells was achieved with an over 100-fold decreased clinical dose of DOX. [52] Moreover, the excellent tumor tropic and permeability traits of MSCs-TDDSs have led to their broad application in targeted drug delivery to diverse primary tumors and their xenografts, including gastric cancer, [53] breast cancer, [54] liver cancer, [55] colon cancer, [12d] tongue squamous cell carcinoma, [56] fibrosarcoma, [57] and other cancer types; these systems show dramatic advantages in efficient and precise drug delivery to tumor cells. [12d,17b] For example, Kang et al demonstrated significantly increased distribution of gold nanoparticles in fibrosarcoma xenografts when delivered by an MSCs-TDDS; the drug delivery was 37-fold higher than that achieved by intravenous injection of free-gold nanoparticles, resulting in a remarkably enhanced antitumor effect by using photothermal therapy (Figure 3).…”

Thyroid Hormone Effects on Mesenchymal Stem Cell Biology in the Tumour Microenvironment

“…These cells contribute to tissue maintenance and regeneration by their recruitment as "first responders" to sites of tissue injury and inflammation [14]. Tumours, mimicking chronic wounds, hijack the wound healing response to recruit MSCs, among other cells, to help generate the stroma needed for survival and growth [15][16][17][18][19]. The tumour stroma forms the microenvironment in which cancer cells reside and is composed of a heterogeneous population of cells besides MSCs, including cancer-associated fibroblasts (CAFs), pericytes, vascular endothelial cells, and immune cells, in addition to non-cellular components, such as signalling molecules and the extracellular matrix [14,20].…”

“…Further, we engineered MSCs to express the sodium iodide symporter (NIS) reporter gene under the control of a synthetic hypoxia-responsive promoter. NIS is a transmembrane protein that transports iodide, thus allowing quantification and analysis of biodistribution of functional NIS expression by measurement of radioiodide uptake in vitro and in vivo, as well as application of therapeutic radionuclides [18,19,[34][35][36][37][38][39][40]. Stimulation of MSCs transfected with the hypoxia-responsive reporter construct with tumour cell-conditioned medium and cobalt chloride leads to an increase in NISmediated radioiodide uptake activity under T4 and, to a lower extent, T3 stimulation [26,38].…”

“…On a different note, modulation of MSC recruitment and engraftment is of central clinical importance in the context of MSCbased gene delivery in cancer therapy. Based on their natural tropism for solid tumours and metastases, MSCs have been exploited by several groups, including our own, to act as "Trojan horses" that can deliver therapeutic payloads deep into the tumour environment [16,18,19,[35][36][37][38][39][40][53][54][55]. Conditioning of MSCs with thyroid hormones may effectively enhance the potency of gene delivery by MSCs.…”