Interleukin 9 (IL-9) in der immunologischen Krebsabwehr beim malignen Melanom in Mäusen und Patienten
Zusammenfassung der Projektergebnisse
This research fellowship enabled me to study the T cell receptor repertoire and lipid metabolism of human melanoma infiltrating T cells after the originally proposed IL-9 based project focus changed due to severe mouse breeding problems. Recent advances in immunotherapy and targeted drug therapy have dramatically improved the prognosis of metastatic melanoma. Primary melanomas > 1mm thickness are potentially curable by resection but may later recur metastatically. To date, the risk of recurrence of primary melanomas is solely based on histopathological predictors: tumor thickness and ulceration. We aimed to identify a clinically translatable molecular marker to identify patients at high risk for disease progression more accurately. We established that T cell fraction (TCFr, proportion of nucleated cells that are T cells), as measured by high-throughput sequencing of the T cell receptor beta-chain, robustly predicted progression-free survival (PFS). 20% TCFr was the best cut-off to identify patients at risk for progression. Primary melanoma patients with low TCFr had a markedly worse prognosis. To our surprise, TCFr was completely independent of any other predictive variable and the second most powerful predictor after tumor thickness. A TCFr > 20% was protective regardless of ulceration status or mitotic rate and even protective for patients with resected regional nodal disease who had a PFS rate comparable to patients without nodal disease but low TCFr. TCFr was more accurate to predict 5-year PFS than conventional histopathological grading. Therefore, TCFr is the first quantitative molecular test that predicts metastatic recurrence in primary melanoma patients whose disease has been completely resected surgically. This tool could be easily applied in the clinic for more accurate prognostic staging and rational stratification of Stage II and III melanoma patients for therapeutic clinical trials involving adjuvant therapies. Furthermore, we characterized the lipid metabolism of tumor infiltrating T cells in human metastatic melanoma as well as squamous cell carcinoma samples. Fatty acid binding protein 5 (FABP5) was highly upregulated on gene and protein level while other lipid mediators (FABP4, LPL, CD36) were not detectable. FABP5 serves as a lipid receptor and intracellular lipid transporter and might enable tumor infiltrating T cells to survive long-term within the tumor microenvironment. Future functional studies will be conducted by members of Dr. Kupper’s laboratory to understand the effect of FABP5 up-regulation in tumor infiltrating T cells.
Projektbezogene Publikationen (Auswahl)
- High-throughput TCR sequencing helps to predict recurrence in primary melanomas. Skin Inflammation in Human Health and Disease Meeting, June 2018
W. Pruessmann
- Predicting recurrence in primary melanomas by T cell receptor immunosequencing. International Investigative Dermatology Meeting (IID), May 2018
W. Pruessmann, J. Rytlewski, J. Wilmott, M. Mihm Jr., B. Dyring-Andersen, R. Clark, H. Robins, R. Scolyer, T. Kupper
