Reducing resistance to cancer immunotherapy with groundbreaking lipid

cancer immunotherapy

A team of Japanese scientists has potentially discovered an innovative method to reduce a patient’s resistance to cancer immunotherapy.

The team, based at the Hokkaido University, has collaborated with experts at the Aichi Institute of Technology to develop a specially designed lipid nanoparticle that proficiently delivers immune-signalling molecules into liver macrophage cells to mitigate a patient’s resistance to cancer immunotherapy.

Their research, which is published in the Journal for Immunotherapy of Cancer, may have dramatic benefits for cancer patients, enhancing their response to cancer immunotherapy treatment and ultimately saving lives.

Understanding cancer immunotherapy resistance

When checkpoint proteins are activated on the surface of immune cells, they aid in regulating the immune response by stopping them from attacking the other cells in the body. However, some cells are able to hijack this process, which prevents the immune response against them. Scientists have designed special immune checkpoint inhibitors that can overcome this process; however, some patients are still resistant to the treatments.

To combat this resistance, the researchers developed a novel lipid nanoparticle that can effectively transport immunity-triggering molecules into macrophages, which are immune cells that are located in the liver.

Designing a novel lipid

The newly developed lipid, called YSK12-C4, displays a high affinity for immune cells. When the team intravenously administered the lipid into mice with metastatic melanoma, it successfully delivered signalling molecules – named cyclic dinucleotides – throughout 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. Subsequently, they were released into the blood, this time triggering another type of immune cell called natural killer cells in the spleen and lungs, which created interferon-gamma inside the lung metastases.

The team determined that on its own, the treatment only elicited a mild anti-tumour effect due to type 1 interferons and interferon-gamma triggering the expression of a protein called PD-L1. This protein stops a strong tumour-killing immune response of natural killer cells that express PD-1. However, by implementing an anti-PD-1 immunotherapy treatment, the researchers were able to prevent the cancer cells from turning off the natural killer cells, enabling them to launch a full-scale attack.

Takashi Nakamura, from the 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.”

The team are now working on analysing whether the treatment can cause toxicity in the liver or if other signalling molecules can be used.


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