A breach in the protective barrier of pancreatic cancer
Published Feb. 18, 2022 13:49
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Our immune system has the potential to find and destroy cancer cells. However, cancer cells use tricks to avoid the immune system's response.
Professor Douglas Fearon of the Cold Spring Harbor Laboratory and ZhiKai Wang of the University of Science and Technology of China found one such trick. Cancer cells form a protective mantle around them, deactivating the T lymphocytes that they should have eliminated. The discovery of this mechanism offers hope for a new therapeutic approach in the treatment of pancreatic, breast and colon cancer.
Cells of the immune system patrol the body to find tumors and pathogens. If they encounter an intruder, T cells are mobilized to attack. ZhiKai Wang found that this mobilization was turned off by the fusion of three proteins woven into the protective shell that surrounds cancer cells: CXCL12, which usually attracts T cells, the KRT19 protein, and the TGM2 protein, which is responsible for joining the previous two.
Scientists genetically modified them to turn off KRT19 or TGM2 production in mouse pancreatic tumors. Without KRT19 or TGM2, cancer cells lost CXCL12-KRT19 protection and T cells were able to infiltrate and attack. As a result, the pancreatic tumors shrank or disappeared.
Why does this protein envelope shield tumors from T cells? Wang explains: “This is a bit counterintuitive because CXCL12 are chemokines that attract immune cells. But we found that CXCL12 at extremely high concentrations on the surface of cancer cells does the opposite, immobilizing T cells. ' CXCL12 usually functions as a single protein. But at high concentrations on the surface of cancer cells, together with the KRT19 protein it forms a barrier that significantly reduces T cells.
The study was published in Proceedings of the National Academies of Sciences. In a previous clinical study involving pancreatic cancer patients, Prof. Fearon and colleagues showed that the drug plerixafor (a CXCL12 receptor blocker) increased T-cell infiltration in pancreatic tumor tissues. The current study shows why this immunotherapeutic effect occurs. Fearon and Wang hope that selecting CXCL12 and KRT19 as new therapeutic targets will increase the immune system's chances of killing cancer cells.
Source: CSHL
