Nanoparticles suppress cancer treatment resistance



Artist's impression of nanoparticles destroying a tumour cell.

Nanoparticle innovation is helping to uncover avenues beyond cancer treatment resistance.

Scientists in Japan have designed a lipid nanoparticle that could deliver immune-signalling molecules into liver cells to overcome resistance to anti-tumour immunotherapy.

The approach, led by Hokkaido University and proven in mice experiments, was reported in the Journal for Immunotherapy of Cancer.

‘Checkpoint’ proteins on the surfaces of immune cells help to regulate the body’s immune response by preventing them from indiscriminately attacking other cells.

But some cancer cells are able to hijack this mechanism, preventing an immune response against them.
Recent years have seen the development of ‘immune checkpoint inhibitors’ that can counteract this interaction, but some people are resistant to the treatments.

Now, scientists at Hokkaido University and Aichi Institute of Technology have found a way around this by developing a specially designed lipid nanoparticle that can carry immunity-triggering molecules into immune cells in the liver called macrophages.

The lipid, called YSK12-C4, has a high affinity for immune cells.

When intravenously injected into mice with metastatic melanoma, it was able to deliver signalling molecules, called cyclic dinucleotides, across the cell membranes of their liver macrophages.

Here they stimulated the production of immune-related proteins called type 1 interferons via a stimulator of an interferon gene (STING) pathway.

These were released into the blood, activating another type of immune cell called natural killer cells in the spleen and lung, which produced interferon-gamma inside the lung metastases.

This treatment, on its own, only elicited a mild anti-tumour effect. This is because the type 1 interferons and interferon-gamma triggered the expression of a protein called PD-L1 on the cancer cells.

PD-L1 prevents a strong tumour-killing immune response of natural killer cells that express PD-1. Administering an anti-PD-1 immunotherapy treatment, however, prevented the cancer cells from turning off those natural killer cells, which then became armed and able to launch a full-scale attack.

Takashi Nakamura of Hokkaido University’s faculty of pharmaceutical sciences said: “The findings suggest that our lipid nanoparticles carrying immune-signalling molecules convert the immune status from immunologically cold to immunologically hot.

“This could lead to the development of a promising adjuvant that reduces resistance to anti-PD-1 antibody treatment in some cancer patients.”

Further studies will examine whether the treatment can cause liver toxicity and if different signalling molecules can be used.

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