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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]

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