T cells play a huge role in our immune system's fight against abnormal cells that may develop into cancer. Phagocytes and B cells identify changes in these cells and activate T cells, which then start a full-blown programme of destruction. This works in many cases - unless cancer cells mutate and develop a kind of camouflage undetected by the immune system.
Researchers at University of Freiburg and Leibniz University Hannover (LUH) recently uncovered how a key protein in the "immune escape" process is activated by tumour cells. The team led by Prof. Dr. Maja Banks-Köhn and Prof. Dr. Wolfgang Schamel from the Clusters of Excellence in biological signalling studies (CIBSS and BIOSS) at University of Freiburg and structural biologist Prof. Dr. Teresa Carlomagno from LUH used biophysical, biochemical, and immunological methods in their research. The chemical biologist Banks-Köhn intends to develop medication that intervenes in this specific activation mechanism in order to improve established cancer treatments based on immune checkpoint inhibitors. The research team has recently published their findings in the scientific journal "Science Advances".
Checkpoint inhibitors are therapeutic antibodies connected to the receptors of T cells. Proteins on the surface of T cells such as the immune checkpoint "programmed cell death 1" (PD1) and the signalling pathways triggered by them stop immune responses in healthy bodies. This regulating mechanism prevents inflammatory symptoms such as redness, swelling or fever from worsening. Cancer cells take advantage of such mechanisms to render the body helpless while the cells multiply. Using cell cultures and interaction studies, the researchers discovered that the signalling protein SHP2 in T cells binds to PD1 in two specific places after being activated by a cancer cell signal. This double bond with SHP2 causes the camouflaging effect and switches off the immune cells' response completely.
Antibodies blocking immune inhibitors such as PD1 are both approved treatments for skin melanomas or lung carcinomas and prolong patients' lives. However, as a result, many patients suffer from autoimmune reactions. "Medication that prevents SHP2 and PD1 from binding could be used to reduce side-effects as well as a supplement or alternative to antibody treatments", explains Banks-Köhn. In collaboration with Professor Schamel, she analysed the immune response of B cells and T cells by modifying SHP2 molecules in order to test their predictions based on the crystal structure and magnetic resonance analysis conducted at LUH. Their data illustrates how and in which areas the SHP2 protein binds to PD1, thereby revealing potential target areas for medication. "In our ongoing research project at CIBSS - the Centre for Integrative Biological Signalling Studies - we intend to decode the signalling pathway of PD1 to determine where the proteins are located within the cell, where they bind, and in which time frame the signals operate", explains Banks-Köhn.
Reference: Marasco, et al. (2020) Molecular mechanism of SHP2 activation by PD-1 stimulation. Science Advances. DOI: 10.1126/sciadv.aay4458
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