"Warm up" a cold tumor
There are checkpoint proteins on the surface of immune cells that help regulate the immune response, preventing attacks on healthy cells of the body. But some cancer cells are able to adapt to this mechanism, preventing an immune response against them. Relatively recently, immune checkpoint inhibitors have been developed to help counteract this protective strategy of cancer cells. But for some patients, this treatment is ineffective.
Researchers from Hokkaido University and Aichi Institute of Technology, Japan, have found a way around this problem using specially designed lipid nanoparticles (LNP) that carry a stimulator of the interferon gene signaling pathway (stimulator of an interferon gene, STING) into liver macrophages.
After intravenous administration to mice, lipid nanoparticles (red) are transported through blood vessels (green) and accumulate in the liver.
Lipid YSK12-C4 has a high affinity for immune cells. When administered intravenously to mice with metastatic melanoma, it delivers signaling molecules (cyclic dinucleotides) through the cell membranes of liver macrophages. There they stimulate the production of type 1 interferons through STING. Once in the blood, cyclic dinucleotides activate another type of immune cells – natural T-killers (NK cells) in the spleen and lungs, which produce gamma interferon inside lung metastases.
Mice were injected intravenously with STING-LNP. Getting into the macrophages of the liver, they stimulated the production of interferon-1, which, in turn, activated NK cells in the lungs and spleen. The effect of NK cells is limited to PD-L1; but if STING-LNP is combined with anti-PD-1 therapy, NK cells are able to act fully and destroy cancer cells.
This treatment alone caused only a moderate antitumor effect. The fact is that type 1 interferons and gamma interferon trigger the expression of PD-L1 protein in cancer cells. PD-L1 prevents the tumor-destroying immune response of NK cells expressing PD-1. However, the additional administration of an immunotherapeutic drug against PD-1 did not allow cancer cells to turn off NK cells, which could then launch a full-scale attack.
Combination therapy against PD-1-resistant lung cancer. The combination of antibodies against PD-1 and STING-LNP had the maximum effect in reducing metastases (black areas) in the lungs (pink tissue; far right). STING-LNP in isolation were more effective than antibodies against PD-1 (center left), which, in turn, were no more effective than saline solution (far left).
The results obtained indicate that lipid nanoparticles carrying immune signaling molecules transform the immune status of a tumor from immunologically cold to immunologically hot. This may lead to the development of a promising adjuvant that increases sensitivity to anti-PD-1 treatment in some cancer patients.
Further studies will have to determine whether the treatment is toxic to the liver and whether other signaling molecules can be used.
The article by T.Nakamura et al. STING agonist loaded lipid nanoparticles overcome anti-PD-1 resistance in melanoma lung metastasis via NK cell activation is published in the Journal for ImmunoTherapy of Cancer.
Aminat Adzhieva, portal "Eternal Youth" http://vechnayamolodost.ru based on materials from Hokkaido University: New nano particles suppress resistance to cancer immunotherapy.