Induction of T-helper-17-cell-mediated anti-tumour immunity by pathogen-mimicking polymer nanoparticles.

Abstract

The effectivity of cancer immunotherapies is hindered by immunosuppressive tumour microenvironments that are poorly infiltrated by effector T cells and natural killer cells. In infection and autoimmune disease, the recruitment and activation of effector immune cells is coordinated by pro-inflammatory T helper 17 (T_H17) cells. Here we show that pathogen-mimicking hollow nanoparticles displaying mannan (a polysaccharide that activates T_H17 cells in microbial cell walls) limit the fraction of regulatory T cells and induce T_H17-cell-mediated anti-tumour responses. The nanoparticles activate the pattern-recognition receptor Dectin-2 and Toll-like receptor 4 in dendritic cells, and promote the differentiation of CD4⁺ T cells into the T_H17 phenotype. In mice, intra-tumoural administration of the nanoparticles decreased the fraction of regulatory T cells in the tumour while markedly increasing the fractions of T_H17 cells (and the levels of T_H17-cell-associated cytokines), CD8⁺ T cells, natural killer cells and M1-like macrophages. The anti-tumoural activity of the effector cells was amplified by an agonistic antibody against the co-stimulatory receptor OX40 in multiple mouse models. Nanomaterials that induce T_H17-cell-mediated immune responses may have therapeutic potential.