MDSC Metabolite Found to Underly Immunosuppression, May Aid Cancer Therapy

TUM researchers have found that methylglyoxal underlies MDSC-mediated immunosuppression with implications for cancer diagnosis and treatment.

Although myeloid immune cells with immunosuppressive activity are regarded as important regulators of tumor killing by T cells, until recently, the mechanisms by which a regulatory myeloid cell population known as myeloid-derived suppressor cells (MDSCs) dampens the anti-cancer immune response were poorly characterized.

Researchers from the Institute of Molecular Immunology at the Technical University of Munich have shed light on the phenotype and function of this key immune cell subset, discovering a metabolite that is used by the cells to suppress T cell responses and demonstrating in a mouse model that neutralization of the metabolite could support cancer therapy.

The study, recently published in the journal Nature Immunology under the title, “Regulatory myeloid cells paralyze T cells through cell–cell transfer of the metabolite methylglyoxal,” was by the research teams of co-senior authors Percy Knolle, MD, and Bastian Höchst, PhD.

“The basic consideration for the project was that we observed early on, that MDSCs do not have a “normal” cellular metabolism. Together with our observation that known suppressive pathways seem to play only a minor role, we took a closer look at the metabolism of MDSCs and the effect of their metabolism on T cells,” stated Dr. Höchst.

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“We used a broad variety of methods, including spectral flow cytometry, high resolution microscopy, RNA sequencing, bioinformatic modeling, extracellular flux analysis, mass spectrometry and preclinical models to study the impact of our results for treatment of cancer cells.”

“We discovered a novel principle of immune suppression through myeloid derived suppressor cells that is beyond currently known co-inhibitory molecules. We found that inhibition of anti-tumor immunity was mediated through an inhibitory metabolite that stuns immune cell activation.”

“The discovery of inhibitory metabolites generated as mode-of-action for suppression by myeloid derived suppressor cells. This for the first time identifies a bona fide biomarker for myeloid-derived suppressor cells that is mechanistically involved in immune suppression. Identification of methylglyoxal as inhibitory metabolite that depletes free arginine from cells and blocks arginine signaling moieties in proteins provides a novel concept for highly potent stunning of immune cells,” continued Dr. Höchst.

The researchers plan to further evaluate the significance of the metabolite in cancer and other diseases, possibly as a biomarker to aid diagnoses and prognoses. “Our discovery of methylglyoxal as biomarker for myeloid derived suppressor cells opens new avenues for diagnostics in cancer and diseases associated with chronic inflammation – situations where myeloid derived suppressor cells arise.”

Dr. Höchst’s take-home message: “Local generation of the inhibitory metabolite methylglyoxal shuts down anti-tumor immunity. Targeted inhibition of methylglyoxal glycation activity acts in synergy with checkpoint inhibition to reconstitute anti-tumor immunity.”

Read more about the latest research in the field of immunology.