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Natural Killer T-Cell Agonist ?-Galactosylceramide and PD-1 Blockade Synergize to Reduce Tumor Development in a Preclinical Model of Colon Cancer.


ABSTRACT: Murine and human invariant natural killer T (iNKT) lymphocytes are activated by ?-galactosylceramide (?-GalCer) presented on CD1d. ?-GalCer was first described as a lipid that had strong anti-metastatic effects in a mouse melanoma model, and it has subsequently been shown to induce efficient iNKT cell dependent tumor immunity in several tumor models. We have shown that ?-GalCer treatment leads to a weak reduction of polyp burden in the autochthonous ApcMin/+ mouse model for human colon cancer, however this treatment resulted in upregulation of the inhibitory receptor PD-1 on iNKT cells. While anti-PD-1 treatment can prevent immune-suppression in other cancer types, human colon cancer is generally resistant to this treatment. Here we have used the ApcMin/+ model to investigate whether a combined treatment with ?-GalCer and PD-1 blockade results in improved effects on polyp development. We find that PD-1 expression was high on T cells in polyps and lamina propria (LP) of ApcMin/+ mice compared to polyp free Apc+/+ littermates. Anti-PD-1 treatment alone promoted Tbet expression in iNKT cells and CD4 T cells, but did not significantly reduce polyp numbers. However, the combined treatment with anti-PD-1 and ?-GalCer had synergistic effects, resulting in highly significant reduction of polyp numbers in the small and large intestine. Addition of PD-1 blockade to ?-GalCer treatment prevented loss of iNKT cells that were skewed towards a TH1-like iNKT1 phenotype specifically in polyps. It also resulted in TH1 skewing and increased granzyme B expression of CD4 T cells. Taken together this demonstrates that a combination of immune stimulation targeting iNKT cells and checkpoint blockade may be a promising approach to develop for improved tumor immunotherapy.

SUBMITTER: Wang Y 

PROVIDER: S-EPMC7606378 | biostudies-literature | 2020

REPOSITORIES: biostudies-literature

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Natural Killer T-Cell Agonist α-Galactosylceramide and PD-1 Blockade Synergize to Reduce Tumor Development in a Preclinical Model of Colon Cancer.

Wang Ying Y   Bhave Madhura S MS   Yagita Hideo H   Cardell Susanna L SL  

Frontiers in immunology 20201020


Murine and human invariant natural killer T (iNKT) lymphocytes are activated by α-galactosylceramide (α-GalCer) presented on CD1d. α-GalCer was first described as a lipid that had strong anti-metastatic effects in a mouse melanoma model, and it has subsequently been shown to induce efficient iNKT cell dependent tumor immunity in several tumor models. We have shown that α-GalCer treatment leads to a weak reduction of polyp burden in the autochthonous <i>Apc<sup>Min/+</sup></i> mouse model for hum  ...[more]

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