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Glucocorticoid Receptor-Targeted Nanoliposome for STAT3 Inhibition-Led Myeloid-Derived Suppressor Cell Modulation and
Tithi Bhattacharyya1,2, Pritam Das1,2, Aasia Ansari1,2
1Division of Oils, Lipids Science and Technology, CSIR-Indian Institute of Chemical Technology, Hyderabad 500007, India.
Abstract:
STAT3 is an important protein responsible for cellular proliferation, motility, and immune tolerance and is hyperactive in colorectal cancer, instigating metastasis, cellular proliferation, migration, as well as inhibition. It helps in proliferation of myeloid-derived suppressor cells (MDSCs), which within the tumor microenvironment (TME) suppress T cells to encourage tumor growth, metastasis, and resistance to immunotherapy, besides playing dynamic role in regulating macrophages within the tumor. Thus, MDSC is a potential target to augment immune surveillance within the TME. Herein, we report targeting both colorectal cancer and MDSCs using a glucocorticoid receptor (GR)-targeted nanoliposomal formulation carrying GR-ligand, dexamethasone (Dex), and a STAT3 inhibitor, niclosamide (N). Our main objective was to selectively inhibit STAT3, the key immunomodulatory factor in most TME-associated cells including MDSCs, and also repurpose the use of this antihelminthic, low-cost drug N for cancer treatment. The resultant formulation D1XN exhibited better tumor regression and survivability compared to GR nontargeted formulation. Further, bone marrow cell-derived MDSCs were engineered by D1XN treatment ex vivo and were inoculated back to tumor-bearing mice. Significant tumor growth inhibition with enhanced antiproliferative immune cell signatures, such as T cell infiltration, decrease in Treg cells, and increased M1/M2 macrophage ratio within the TME were observed. This reveals the effectiveness of engineered MDSCs to modulate tumor surveillance besides reversing the aggressiveness of the tumor. Therefore, D1XN and D1XN-mediated engineered MDSCs alone or in combination can be considered as potent selective chemo-immunotherapeutic nanoliposomal agent(s) against colorectal cancer.
Insights
This study developed a nanoliposomal drug delivery system targeting colorectal cancer and myeloid-derived suppressor cells (MDSCs). The formulation enhanced anti-tumor immunity and significantly inhibited tumor growth, offering a new chemo-immunotherapeutic strategy.
Area of Science:
- Oncology
- Immunology
- Nanotechnology
Background:
- Signal transducer and activator of transcription 3 (STAT3) is hyperactive in colorectal cancer, promoting tumor growth and immune suppression.
- Myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment (TME) inhibit anti-tumor T cell responses and contribute to immune tolerance.
- Targeting STAT3 and MDSCs presents a potential strategy to enhance anti-tumor immunity in colorectal cancer.
Purpose of the Study:
- To develop and evaluate a novel nanoliposomal formulation (D1XN) for targeted delivery of dexamethasone (Dex) and niclosamide (N) to inhibit STAT3 in colorectal cancer and MDSCs.
- To investigate the efficacy of D1XN in inhibiting tumor growth and modulating the immune landscape within the TME.
- To assess the potential of D1XN-engineered MDSCs as a chemo-immunotherapeutic agent against colorectal cancer.
Main Methods:
- A glucocorticoid receptor (GR)-targeted nanoliposomal formulation (D1XN) encapsulating Dex and niclosamide was synthesized.
- Ex vivo treatment of bone marrow-derived MDSCs with D1XN followed by inoculation into tumor-bearing mice.
- Evaluation of tumor regression, survivability, T cell infiltration, regulatory T cell (Treg) levels, and macrophage polarization (M1/M2 ratio) in the TME.
Main Results:
- The D1XN formulation demonstrated superior tumor regression and enhanced survivability compared to non-targeted formulations.
- D1XN treatment of MDSCs ex vivo and their subsequent re-administration led to significant tumor growth inhibition.
- Engineered MDSCs promoted enhanced anti-tumor immune signatures, including increased T cell infiltration, reduced Treg cells, and a higher M1/M2 macrophage ratio in the TME.
Conclusions:
- D1XN effectively targets colorectal cancer and MDSCs, inhibiting STAT3 and reversing tumor-promoting immune suppression.
- D1XN-mediated engineered MDSCs can modulate tumor surveillance and reduce tumor aggressiveness.
- The D1XN formulation and D1XN-engineered MDSCs represent promising selective chemo-immunotherapeutic agents for colorectal cancer treatment.
