Natural Killer T-Cell Agonist α-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 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 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 α-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 α-GalCer had synergistic effects, resulting in highly significant reduction of polyp numbers in the small and large intestine. Addition of PD-1 blockade to α-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.

• Authors: Ying Wang, Madhura S Bhave, Hideo Yagita, Susanna L Cardell
• Journal: Frontiers in immunology (Front Immunol) Vol. 11 Pg. 581301 ( 2020) ISSN: 1664-3224 [Electronic] Switzerland
• PMID: 33193386 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2020 Wang, Bhave, Yagita and Cardell.

Chemical References

• Adenomatous Polyposis Coli Protein
• Antibodies, Blocking
• Galactosylceramides
• Pdcd1 protein, mouse
• Programmed Cell Death 1 Receptor
• adenomatous polyposis coli protein, mouse
• alpha-galactosylceramide

Topics

• Adenomatous Polyposis Coli Protein (deficiency, genetics)
• Animals
• Antibodies, Blocking (administration & dosage)
• Colonic Neoplasms (immunology, prevention & control)
• Female
• Galactosylceramides (administration & dosage)
• Humans
• Intestinal Mucosa (immunology)
• Intestinal Polyps (immunology, prevention & control)
• Macrophages (immunology)
• Male
• Mice
• Mice, Inbred C57BL
• Mice, Mutant Strains
• Natural Killer T-Cells (immunology)
• Neoplasms, Experimental (immunology, prevention & control)
• Programmed Cell Death 1 Receptor (antagonists & inhibitors, immunology)
• T-Lymphocytes, Regulatory (immunology)
• Th1 Cells (immunology)