Oncologists have had great success with cancer immunotherapy in recent years, especially with the approach known as immune checkpoint inhibition, which was recognized with last year's Nobel prize for medicine. Tumor cells have the ability to curb the activity of patients' own T cells, causing the T cells to leave the tumor alone. To do this, they use a molecular "handshake", where molecules on the surface of tumor cells interact with checkpoint molecules, as they are known, on the surface of T cells. However, if patients are administered particular antibodies (checkpoint inhibitors) that render this interaction impossible, the T cells can attack and eliminate the tumor.
One of the key checkpoint molecules is PD-1. Until now, there had been little research into just how the PD-1 handshake signal is transmitted within T cells to prevent the cells being activated. A team of scientists has now taken a closer look at important molecules in the biochemical signalling pathway of PD-1, including the enzyme SHP-2,a protein-tyrosine phosphatase.
Cancer researchers are targeting this enzyme to further increase the efficacy of cancer immunotherapy. The scientists have now shown that when SHP-2 is lacking, a related molecule, SHP-1, performs its role. "SHP-1 and SHP-2 can replace each other," says the lead author. "So it's not enough to attack just one of these molecules - you have to target both simultaneously."
To ascertain which molecules in fact interact with the PD-1 surface molecule, the researchers conducted experiments with mouse T cells, isolating the PD-1 molecule and several dozen molecules that bind to PD-1. They were able to identify these molecules using SWATH-MS, a mass spectrometry approach. The PD-1-SHP-1 and PD-1-SHP-2 complexes, authors show that both dampen the TCR and CD28 signaling pathways equally. Therefore, the study illustrates how comparison of coinhibitory receptor signaling via quantitative interactomics in primary T cells unveils their extent of redundancy and provides a rationale for designing combinations of blocking antibodies in cancer immunotherapy on the basis of undisputed modes of action..
Redundancies in T cells
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