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New Nanoparticles Suppress Resistance to Cancer Immunotherapy
A lipid nanoparticle has been specially designed to deliver immune-signalling molecules into liver macrophage cells to overcome resistance to anti-tumour immunotherapy.

Cancer patients today have far more treatment options than they did a decade ago, with some showing remarkable effects and being able to completely eradicate tumours despite having spread throughout the body. However, for many patients, nearly all presently available treatments face the same problem: they ultimately stop working due to drug resistance.

In recent years, resistance to immune checkpoint inhibitors has emerged to become one of the greatest obstacles in cancer immunotherapy. Normally, checkpoint proteins located on the surfaces of immune cells are activated to help prevent our immune system from indiscriminately attacking our bodies’ healthy cells. But some cancer cells have evolved to hijack this mechanism, thus preventing them from being targeted by immune cells. To counteract this bypassing effect, scientists have developed immune checkpoint inhibitors. Yet, it has been found that some people are resistant to these treatments.

As an alternative solution, a team of scientists at Hokkaido University and Aichi Institute of Technology have developed a specially engineered lipid nanoparticle, called YSK12-C4, that can carry immunity-triggering molecules into macrophages in the liver, effectively replacing the function of immune checkpoint inhibitors and opening a new door to aid patients in overcoming immunotherapy resistance.

In the study, lead author Takashi Nakamura and his colleagues designed lipid nanoparticles that have a high affinity for immune cells and engineered them to carry signalling molecules, known as cyclic dinucleotides, which stimulate an interferon gene. When intravenously injected into mice with metastatic melanoma, they found that the lipid can deliver the cyclic dinucleotides across the cell membranes of liver macrophages to stimulate the production of immune-related proteins called type 1 interferons via a stimulator of an interferon gene (STING) pathway. When these proteins were released into the bloodstream, they activated natural killer cells in the spleen and lung, which produced interferon-gamma, a primary activator of macrophages, inside the lung metastases.

On its own, this STING agonist treatment only triggered 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 suppresses the strong tumour-killing immune response of natural killer cells that express PD-1. However, when the team administered the STING agonist treatment together with an anti-PD-1 immunotherapy treatment, they successfully prevented the cancer cells from turning off those natural killer cells, thereby allowing them to become fully armed and target the cancer cells.

“The findings suggest that our lipid nanoparticles carrying immune-signalling molecules convert the immune status from immunologically cold to immunologically hot,” says Takashi Nakamura of Hokkaido University’s Faculty of Pharmaceutical Sciences. “This could lead to the development of a promising adjuvant that reduces resistance to anti-PD-1 antibody treatment in some cancer patients.”

Although further studies are still needed to confirm the safety and efficacy of the treatment, the researchers are hopeful that the STING agonist treatment can become a promising adjuvant to be used in combination therapy to treat anti-PD-1-resistant tumours. The team will further investigate whether the treatment can cause liver toxicity and if different signalling molecules can be used.

Source: Nakamura et al. (2021). STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation. Journal for ImmunoTherapy of Cancer, 9(7), e002852

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