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Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities.

ABSTRACT: Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive, although they often show signs of prior clonal expansion. Hypothesizing that this may be due to peripheral tolerance, we formulated nanoparticles containing innate immune stimulants that we found were sufficient to activate self-specific CD8+ T cells and injected them into two different mouse tumor models, B16F10 and MC38. These nanoparticles robustly activated and/or expanded antigen-specific CD8+ tumor-infiltrating T cells, along with a decrease in regulatory CD4+ T cells and an increase in Interleukin-17 producers, resulting in significant tumor growth retardation or elimination and the establishment of immune memory in surviving mice. Furthermore, nanoparticles with modification of stimulating human T cells enabled the robust activation of endogenous T cells in patient-derived tumor organoids. These results indicate that breaking peripheral tolerance without regard to the antigen specificity creates a promising pathway for cancer immunotherapy.

SUBMITTER: Yin Q

PROVIDER: S-EPMC8166076 | biostudies-literature | 2021 May

REPOSITORIES: biostudies-literature

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Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities.

Yin Qian Q Yu Wong W Grzeskowiak Caitlin L CL Li Jing J Huang Huang H Guo Jing J Chen Liang L Wang Feng F Zhao Fan F von Boehmer Lotta L Metzner Thomas J TJ Leppert John T JT Chien Yueh-Hsiu YH Kuo Calvin J CJ Kuo Calvin J CJ Davis Mark M MM

Proceedings of the National Academy of Sciences of the United States of America 20210501 21

Tumors are often infiltrated by T lymphocytes recognizing either self- or mutated antigens but are generally inactive, although they often show signs of prior clonal expansion. Hypothesizing that this may be due to peripheral tolerance, we formulated nanoparticles containing innate immune stimulants that we found were sufficient to activate self-specific CD8<sup>+</sup> T cells and injected them into two different mouse tumor models, B16F10 and MC38. These nanoparticles robustly activated and/or ...[more]

PMID: 34021082

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Project description:Understanding biobased nanocomposites is critical in fabricating high performing sustainable materials. In this study, fundamental nanoparticle assembly structures at the nanoscale are examined and correlated with the macroscale properties of coatings formulated with these structures. Nanoparticle assembly mechanisms within biobased polymer matrices were probed using in situ liquid-phase atomic force microscopy (AFM) and computational simulation. Furthermore, coatings formulated using these nanoparticle assemblies with biobased polymers were evaluated with regard to the hydrophobicity and adhesion after water immersion. Two biobased glycopolymers, hydroxyethyl cellulose (HEC) and hydroxyethyl starch (HES), were investigated. Their repeating units share the same chemical composition and only differ in monomer conformations (α- and β-anomeric glycosides). Unique fractal structures of silica nanoparticle assemblies were observed with HEC, while compact clusters were observed with HES. Simulation and AFM measurement suggest that strong attraction between silica surfaces in the HEC matrix induces diffusion-limited-aggregation, leading to large-scale, fractal assembly structures. By contrast, weak attraction in HES only produces reaction-limited-aggregation and small compact cluster structures. With high particle loading, the fractal structures in HEC formed a network, which enabled a waterborne formulation of superhydrophobic coating after silane treatment. The silica nanoparticle assembly in HEC was demonstrated to significantly improve adhesion, which showed minimum adhesion loss even after extended water immersion. The superior performance was only observed with HEC, not HES. The results bridge the assembly structures at the nanoscale, influenced by molecular conformation of biobased polymers, to the coating performance at the macroscopic level. Through this study we unveil new opportunities in economical and sustainable development of high-performance biobased materials.

Dataset Information

Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities.

Publications

Nanoparticle-enabled innate immune stimulation activates endogenous tumor-infiltrating T cells with broad antigen specificities.

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