Project Title: Transcriptional modules exposing related therapeutic vulnerabilities in melanoma
PhD Award Expected: Summer 2020
I am from a country where you can taste the greatest custard pastry, listen to Fado, get crazy about football and enjoy great weather all year round: Portugal.
I did a Masters in Molecular Biology and Genetics in the Faculty of Sciences, University of Lisbon. I developed my thesis in the European Molecular Biology Laboratory in Italy, in chromosomal instability and aneuploidy.
I bumped into science because of my dad, who surrounded me with biology books and scientific magazines, allowing me to realize how amazing this field is. From then onwards my academic and professional career have been developing like a snowball, until I ended up having the great opportunity to join MELGEN network.
I am passionate about almost all kinds of science, but molecular science and particularly cancer amaze me.
But my life is not only about science and I like to enjoy whatever it has to offer. In my free time I like to travel, hang out with my family and friends, play sports, such as basketball and swimming, go to the movies, read, and, coming from Portugal, it would be impossible not to say this part: eat good food!
Melanoma is one of the most immunogenic tumor diseases with known cases of spontaneous tumor regression and frequent presence of tumor infiltrated lymphocytes (TILs). For this reason, melanoma cells provide a suitable model to investigate the molecular crosstalk of cancer cells with cells of the immune system. Advances in this field have allowed the development of efficient therapeutic strategies and a major revolution in the clinical management of metastatic melanoma patients with introduction of immune checkpoint blockade (ICB) as primary choice of therapy. The main ICB modalities used in the clinical setting are targeting immune checkpoint molecules, such as CTLA-4 and PD1, in order to prevent the T cell inhibitory signals mediated by these molecules, and thus boost the immune response against the tumor cells. Although clinical benefit is frequent, still about 60% of patients develop primary resistance, whereas others experience initial clinical response and later on develop secondary resistance.
Considering this, this project aimed to understand the role of different immune cell subsets and of the immune system as a whole, in melanoma, to define immune profiles and their prognostic value in metastatic melanoma tumors and finally, to derive gene expression signatures applicable to tumors from patients receiving targeted therapy and immunotherapy.
Four works were developed, in order to achieve these aims:
In study I we have used a cohort of metastatic melanomas collected prior to checkpoint inhibitor era and found that the presence of intra-tumoral lymphocytes is associated with improved survival. The presence of CD20+ B cells was frequently concomitant with CD3+/CD8+ T cells, indicating the formation of tertiary lymphoid structures (TLS). The TLS gene signature predicted clinical outcome in patients treated with immune checkpoint inhibitors. We were able to identify the presence of activated and immature B cells in these structures, which supports their functional role in melanoma tumors.
In study II we have used immune cell type associated DNA methylation based signatures on a large cohort of metastatic melanoma tumors. We found three distinct immune clusters for metastatic melanoma that significantly associates with patient survival. Additionally, these DNA methylation signatures showed prognostic implications in other solid tumor cohorts.
In study III we aimed to understand the role of PTEN in prognosis, therapy response and immune escape in melanoma. We confirmed in our cohort that PTEN alterations promote immune evasion highlighted by decreased frequency of T cell infiltration in such tumors, resulting in a worse patient survival. More importantly, our results suggest that dedifferentiated PTEN negative melanoma tumors have poor patient outcome, no T cell infiltration and transcriptional properties rendering them resistant to targeted- and immunotherapy.
In study IV, we aimed to identify immune cell subtypes and its associated markers using scRNA-Seq data and used these markers to create a composite score to predict treatment response in the tumor-derived bulk RNA-Seq data. We have used single-cell RNA-Seq derived immune signatures representing several immune cell populations, and applied them to different datasets, confirming their prognostic value in metastatic melanoma.
Overall, these four projects suggest that distinct molecular and transcriptional properties may predict poor clinical benefit of both targeted therapy and immune checkpoint blockade agents in melanoma.
Phung B, Cieśla M, Sanna A, Guzzi N, Beneventi G, Cao Thi Ngoc P, Lauss M, Cabrita R, Cordero E, Bosch A, Rosengren F, Häkkinen J, Griewank K, Paschen A, Harbst K, Olsson H, Ingvar C, Carneiro A, Tsao H, Schadendorf D, Pietras K, Bellodi C, Jönsson G. The X-Linked DDX3X RNA Helicase Dictates Translation Reprogramming and Metastasis in Melanoma. Cell Rep. 2019 Jun 18;27(12):3573-3586.e7. Available at: https://www.sciencedirect.com/science/article/pii/S2211124719306989
Cabrita R, Lauss M, Sanna A, Donia M, Skaarup Larsen M, Mitra S, Johansson I, Phung B, Harbst K, Vallon-Christersson J, van Schoiack A, Lövgren K, Warren S, Jirström K, Olsson H, Pietras K, Ingvar C, Isaksson K, Schadendorf D, Schmidt H, Bastholt L, Carneiro A, Wargo JA, Svane IM, Jönsson G. Tertiary lymphoid structures improve immunotherapy and survival in melanoma. Nature. 2020 Jan;577(7791):561-565. Available at: https://www.nature.com/articles/s41586-019-1914-8
Mitra S, Lauss M, Cabrita R, Choi J, Zhang T, Isaksson K, Olsson H, Ingvar C, Carneiro A, Staaf J, Ringnér M, Nielsen K, Brown KM, Jönsson G. Analysis of DNA methylation-based tumour immune microenvironment patterns in metastatic melanoma. Mol Oncol. 2020 Mar 9; doi:10.1002/1878-0261.12663. https://febs.onlinelibrary.wiley.com/doi/10.1002/1878-0261.12663