Monitoring treatment response in lung cancer patients with glycodelin

Patients have regular check-ups during and after lung cancer treatment to see whether the treatment is successful in the long term – or whether the cancer has returned. This is extremely important for both the treating physicians as well as the patients. A DZL research team has now discovered that the presence of the protein glycodelin in the blood indicates that a therapy is failing. This leads to some interesting conclusions.

Immunotherapies reactivate the body’s own defences to fight a tumor. For non-small cell lung cancer (NSCLC), the survival times of patients treated in this way improved significantly. However, immunotherapy does not work for everyone. This suggests that additional mechanisms are involved.

Early results from Heidelberg

In earlier studies, scientists from the DZL site TLRC Heidelberg had already established that lung tumors produce the mRNA for glycodelin. Women with such tumors have a reduced survival rate. The physiological function of the glycodelin protein is to downregulate the maternal immune system of the uterus at the beginning of pregnancy. This is necessary to prevent it from recognizing the fetus as ‘foreign’. Tumors take advantage of this function by upregulating the production of glycodelin.

New findings on the mode of action of glycodelin

The aim of the new study was to investigate the underlying mechanisms of action of glycodelin in more detail. To this end, the Heidelberg researchers teamed up with scientists from the Borstel Research Center at the DZL site ARCN. Together, they were able to show that glycodelin binds strongly to certain subgroups of immune cells and thus influences various signaling pathways. Genes associated with inflammatory processes or the tumor environment were deregulated. Multiplex immunofluorescence staining, which allows the parallel detection and spatial localization of a large number of surface proteins, revealed that these immune cells include CD8-positive T lymphocytes. It is precisely these T cells – also known as “cytotoxic” – that play an important role in immunotherapies. It is conceivable that glycodelin blocks their effect and thus contributes to treatment failure.  

Clinical potential

Further studies have now shown that glycodelin can also be found in the blood of both male and female patients. There was a clear link between high levels and early tumor recurrence – but only in women. Glycodelin therefore contributes to the suppression of the immune system and thus to the recurrence of the tumor.

This marks out Glycodelin as an important sex-specific marker that could be used in therapy monitoring. It is also conceivable to develop an antibody that blocks glycodelin. In this way, the tumor could be deprived of one of the options of evading therapy. Dr. Sebastian Marwitz from the Research Center Borstel is optimistic: “The results on the sex-specific role of glycodelin offers an excellent first step towards precision medicine and targeted treatment for female patients.” Head of the study Dr. Marc Schneider from the Thoraxklinik Heidelberg adds: “In addition to the checkpoint inhibitors of immunotherapy, blocking the binding of glycodelin to immune cells thus represents an alternative way of combating the tumor.”

Successful cooperation within the DZL

These new insights gained were achieved through a collaboration between scientists from the German Cancer Research Center, the Thoraxklinik and the University of Heidelberg (all three belong to DZL site TLRC) and the Research Center Borstel (DZL site ARCN). It was published earlier this month in the journal Translational Research. The publication’s first author, Sarah Richtmann, was supported by the Mobility Grant Program of the DZL Academy.

 

Source: Richtmann S, Marwitz S, Muley T, Koistinen H, Christopoulos P, Thomas M, Kazdal D, Allgäuer M, Winter H, Goldmann T, Meister M, Klingmüller U, Schneider MA (2024) The pregnancy-associated protein glycodelin as a potential sex-specific target for resistance to immunotherapy in non-small cell lung cancer. Translational Research (ARCN, TLRC) https://doi.org/10.1016/j.trsl.2024.02.007

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