P-03.02 The prognostic role of glycodelin through the interaction with the tumor microenvironment in NSCLC

<h3>Background</h3> Lung cancer ranks among the most frequently diagnosed cancers globally and was the primary cause of cancer-related death in 2020. Current lung cancer therapies aim to activate the immune system through checkpoint inhibitors, interrupting the suppressive interaction of tumor cells with the local immune system. However, only approximately 30% of the patients benefit from an immunotherapy due to therapy resistance. Therefore, new therapeutic targets are needed. Recent research has shown that glycodelin, a protein regulating various processes such as immunosuppression, fertilization and implantation during pregnancy, is also expressed in several cancers including non-small cell lung cancer (NSCLC). A significant increase of glycodelin levels in female patients receiving immunotherapy was linked to shorter progression-free survival. However, the processes how glycodelin regulates the immune system in the tumor microenvironment (TME) and the link between glycodelin, patient response and treatment outcome has not been investigated up to now. <h3>Materials and Methods</h3> For this, we performed spatial analyses on tissue microarrays (TMAs) covering 450 patients who underwent surgery at Thoraxklinik-Heidelberg. These TMAs were stained by multiplex immunofluorescence using 5-plex panels for macrophage and T cell characterization, respectively. The staining of the different cell markers was analyzed in regard to colocalization and distances to each other. <h3>Results</h3> We confirmed that glycodelin not only has a general negative influence on the overall survival of the patients, but it also co-localized with certain immune cells. Furthermore, a negative correlation between glycodelin levels and the number of neuronal nitric oxide synthase (iNOS) positive cells was observed. Cells positive for the M1 macrophage marker iNOS have in general a positive influence on the overall survival of the patients. This association was independent of co-localization with glycodelin. Co-localization of glycodelin with cells positive for the M2 macrophage marker CD163 resulted in a significant negative association to the overall survival of the patients. In contrast, glycodelin negative M2 macrophages did not affect the overall survival of the patients. Performing spatial analyses between tumor cells and macrophages showed that glycodelin levels correlated in a negative manner to the distance between panCK positive cells and M1 macrophages. <h3>Conclusions</h3> Taken together, our data suggest an interaction of glycodelin with macrophages. This interaction seems to drive macrophages into an M2-like state, resulting in a more pro-tumorigenic state of the TME and leading to a worse outcome for the patients. Targeting glycodelin in a therapeutic approach could therefore help to remodel the TME and overcome macrophage-mediated immunosuppression. L. Strotmann: None. S. Richtmann: None. S. Marwitz: None. L.V. Klotz: None. M. Allgäuer: None. T. Goldmann: None. M. Meister: None. U. Klingmüller: None. M.A. Schneider: None.