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Mapping Cell Composition of Metastatic Melanoma To Identify Cause of Immunotherapy Resistance

By: Joanna Pozniak, Dennis Pedri, Ewout Landeloos, Yannick Van Herck, Asier Antoranz, Lukas Vanwynsberghe, Ada Nowosad, Niccolò Roda, Samira Makhzami, Greet Bervoets, Lucas Ferreira Maciel, Carlos Ariel Pulido-Vicuña, Lotte Pollaris, Ruth Seurinck, Fang Zhao, Karine Flem-Karlsen, William Damsky, Limin Chen, Despoina Karagianni, Sonia Cinque, Jean-Christophe Marine



Immunotherapy, a revolutionary cancer treatment leveraging the body's immune system, has shown significant success in advanced skin cancer, particularly melanoma. Despite this, only around 50% of cancer patients respond to immunotherapy, and the reasons for this resistance are unclear.


image of Human metastatic melanoma biopsy (red = cancer cells, blue and green = stromal cells)
image of Human metastatic melanoma biopsy (red = cancer cells, blue and green = stromal cells)

In our unique longitudinal study, we focused on melanoma patients undergoing immune checkpoint blockade (ICB) therapy, collecting samples before and after the initial 2 to 3-week treatment cycle.

Employing single-cell RNA sequencing, we aimed to comprehensively characterize cancer cells within tumors and understand their spatial distribution. 


Our findings revealed the diversity of melanoma tumors, influenced by neighboring cells. We identified Mesenchymal-like cells as rare but predictive of immune therapy response, suggesting their role in treatment resistance. Crucially, we identified TCF4 as a key regulator of this cell state and proposed a strategy using a BET inhibitor drug to enhance immunotherapy response, showing promise in mouse models.


“VSC was essential in this study, because to analyse and store the large sequencing and imaging data from many patients we needed a reliable and accessible high performance computing infrastructure. VSC was perfectly suited for fast and parallel execution of computational tasks.” 

This research was possible by the generosity of melanoma patients recruited in UZ Leuven and funding from organizations like the Grand Challenges Program of VIB, FWO, Marie Sklodowska-Curie fund, and Stichting tegen Kanker, opens new avenues to improve immunotherapy outcomes and broaden its application in cancer treatment.


 

Read the full publication in ScienceDirect here

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