Stimulating the Immune System to Fight Cancer

Cancer cells have developed strategies to evade surveillance by the immune system and to prevent immune response.

In recent years, fighting cancer with the help of the immune system has entered into clinical practice and gained increasing importance as a therapeutic approach. Current therapies apply so-called immune checkpoint inhibitors.. Targeting these checkpoints can release this tumor-induced brake. Another strategy developed by cancer cells to escape the immune response is the production of the enzyme indoleamine-2,3-dioxygenase (IDO1), which metabolizes tryptophan into kynurenine and thereby interferes with the immune response in two ways: 

1. The depletion of tryptophan negatively impacts the growth of T cells, a central component of the immune response, which seek out and block cancer cells. 
2. The produced kynurenin inhibits T cells in the immediate environment of the cancer cells.

New Inhibitors against IDO1 — The Quest is on

IDO1 is in the focus of pharmaceutical research because of its cancer-driving effect. However, it has not yet been possible to prove whether the inhibitor really blocks IDO1 in the tumor and whether the used dose is sufficient.

Elisabeth Hennes, PhD student at the MPI and first author of the study, employed a sensor that measures the conversion of the IOD1 substrate tryptophan into the metabolic product kynurenine in cell culture and thereby detects IDO1 activity. Based on this test strategy, several highly potent inhibitors with different mechanisms of action were identified from a library of more than 150,000 chemical substances: These include substances that directly switch off IDO1 as well as indirect inhibitors that prevent the production of IDO1 itself or that of its important cofactor heme.

“Unfortunately, previous attempts to find a compound that effectively stops the cancer-promoting activity of IDO1 in tumors have met with little success. However, the development of new compounds that can switch off IDO1 via different mechanisms of action could be a promising approach for immunotherapies in the fight against cancer. We hope that our newly developed cell-based assay could contribute to this area of research,” says Slava Ziegler.

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Sources:

Herbert Waldmann, Elisabeth Hennes, Philipp Lampe, Lara Dötsch, Nora Bruning, Lisa-Marie Pulvermacher, Sonja Sievers, Slava Ziegler. Cell‐Based Identification of New IDO1 Modulator Chemotypes. Angewandte Chemie International Edition, 2021; DOI: 10.1002/anie.202016004

Max Planck Institute of Molecular Physiology. “Stimulating the immune system to fight cancer.” ScienceDaily. ScienceDaily, 17 March 2021. <www.sciencedaily.com/releases/2021/03/210317111741.htm>.

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