How to clear the way for T cells
To break through the sugar shield of a cancerous tumor
Immunotherapy with CAR-T cells showed excellent results against blood cancer, but was not very effective against solid tumors. Scientists from Milan, Italy, have suggested that it's the sugar coating that solid tumors cover themselves with: a shield of sugar prevents CAR-T cells from getting close to tumor cells. To clear the way for T-cells to the tumor, Italian researchers are developing a kind of molecular torpedo to crack the sugar shield.
CAR-T are chimeric T cells. Initially, they are taken from the patient himself, then subjected to genetic modification to induce expression on its surface of a receptor that can identify and destroy cancer cells, and then injected back into the patient's body.
Despite many years of research, medical scientists have not yet been able to create a CAR-T therapy that works as effectively against solid tumors as against hematological malignancies. The researchers consider glycosylation of the surface of cancer cells in solid tumors to be the main obstacle.
"Immunotherapy with chimeric antigen-receptor T cells has shown exceptional success in patients with refractory B-cell malignancies," says Beatrice Greco, senior author of the study. — However, the first studies on people with solid tumors revealed unique obstacles to demonstrating good efficacy. Understanding the determinants of tumor recognition by CAR-T cells should lead to the development of strategies that can overcome this resistance."
Greco and her colleagues looked for what different cancers that are difficult to destroy with CAR-T have in common, and found that these resistant tumors "express extracellular N-glycans, the abundance of which negatively correlates with the effectiveness of CAR-T cells." Using simple sugars, the cancer cell forms oligosaccharides from them, and then, with the help of a special enzyme, catalyzes the transfer of the oligosaccharide to the amino acid acceptor, which in this case is asparagine. In the end, a dense chain of sugar molecules builds a real fortress wall around the cancer cell.
To solve this problem, Greco's team used 2-deoxy-D-glucose, a glucose analog that is picked up by glucose transporters of the cancer cell membrane like regular glucose, but cannot undergo further glycolysis. Thus, the process of N-glycosylation is inhibited and a gap appears in the sugar shield of the cancer cell. Cells with a destroyed sugar coating become more vulnerable to CAR-T therapy. Experiments on mice showed that exposure to 2-deoxy-D-glucose on solid tumors of the pancreas and bladder sensitized the latter, i.e. increased their sensitivity to the effects of CAR-T.
"In general, our results show that tumor N-glycosylation regulates the quality and strength of CAR-T cell reactions, paving the way for the rational development of improved methods for the treatment of solid malignant neoplasms," concluded Beatrice Greco.
Article by Greco et al. Disrupting N-glycan expression on tumor cells boosts chimeric antigen receptor T cell efficacy against solid malignancies is published in the journal Science Translational Medicine.
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