Tumor Microenvironment Immunomodulation By Nanoformulated TLR 7/8 Agonist And PI3k Delta Inhibitor Enhances Therapeutic Benefits Of Radiotherapy

Author

Mostafa Yazdimamaghani, Missouri University of Science and TechnologyFollow
Oleg V. Kolupaev
Chaemin Lim
Duhyeong Hwang
Sonia J. Laurie
Charles M. Perou
Alexander V. Kabanov
Jonathan S. Serody

Abstract

Infiltration of immunosuppressive cells into the breast tumor microenvironment (TME) is associated with suppressed effector T cell (Teff) responses, accelerated tumor growth, and poor clinical outcomes. Previous studies from our group and others identified infiltration of immunosuppressive myeloid-derived suppressor cells (MDSCs) and regulatory T cells (Tregs) as critical contributors to immune dysfunction in the orthotopic claudin-low tumor model, limiting the efficacy of adoptive cellular therapy. However, approaches to target these cells in the TME are currently lacking. To overcome this barrier, polymeric micellular nanoparticles (PMNPs) were used for the co-delivery of small molecule drugs activating Toll-like receptors 7 and 8 (TLR7/8) and inhibiting PI3K delta (PI3Kδ). The immunomodulation of the TME by TLR7/8 agonist and PI3K inhibitor led to type 1 macrophage polarization, decreased MDSC accumulation and selectively decreased tissue-resident Tregs in the TME, while enhancing the T and B cell adaptive immune responses. PMNPs significantly enhanced the anti-tumor activity of local radiation therapy (RT) in mice bearing orthotopic claudin-low tumors compared to RT alone. Taken together, these data demonstrate that RT combined with a nano formulated immunostimulant diminished the immunosuppressive TME resulting in tumor regression. These findings set the stage for clinical studies of this approach.

Recommended Citation

M. Yazdimamaghani et al., "Tumor Microenvironment Immunomodulation By Nanoformulated TLR 7/8 Agonist And PI3k Delta Inhibitor Enhances Therapeutic Benefits Of Radiotherapy," Biomaterials, vol. 312, article no. 122750, Elsevier, Jan 2025.

The definitive version is available at https://doi.org/10.1016/j.biomaterials.2024.122750

Department(s)

Chemical and Biochemical Engineering

Publication Status

Open Access

Comments

University of North Carolina at Chapel Hill, Grant P50-CA058223

Keywords and Phrases

Cancer immunotherapy; Drug delivery; Immunomodulation; Nanomedicine; Radioimmunotherapy; Tumor microenvironment

International Standard Serial Number (ISSN)

1878-5905; 0142-9612

Document Type

Article - Journal

Document Version

Citation

File Type

text

Language(s)

English

Rights

© 2025 Elsevier, All rights reserved.

Publication Date

01 Jan 2025

PubMed ID

39126779