Project Title: Dissecting the role of the immune system and stroma in melanoma development
PhD Awarded: January 2020
I am Swedish, but originally from China, and currently doing my PhD in David Adam’s group at the Wellcome Trust Sanger Institute in Cambridge, UK. Before starting my PhD, I completed a M.Sc in biotechnology engineering at Lund University in Sweden, followed by a 2 year industrial research graduate programme (IMED) at AstraZeneca.
Research is my biggest passion, and I am particularly interested in the connection between cancer and immunology. I want to understand how tumours manage to escape the immune system, and my hope is that this knowledge can lead to development of new drugs for treatment of cancers.
Outside of science, I spend a lot of time in the kitchen, experimenting with new recipes or exploring different combinations.What also gives me lots of energy and positive endorphins is exercising; whether it is the gym, classes, running or spinning.
The primary goal of my project was to understand how genetic alterations (changes in DNA) shape melanoma as a disease: from the biological processes that govern tumour development to how tumours evolve and escape immune regulation. Studying these changes could therefore help refine our understanding of melanoma progression with the added potential to offer new perspectives for disease management.
Due to the significant diversity present across melanomas, it is important to study the genetic differences between different patients’ tumours. This can be done, for instance, by comparing which genes or biological pathways are commonly mutated, by studying histopathological subtypes or degree of sun exposure. Ultimately, genetic changes could also have a prognostic impact, which could help researchers understand what factors play a role in making a tumour particularly aggressive and assist doctors in deciding what treatments to prescribe any given patient.
We have learnt a great deal about melanoma genetics through large collaborative studies in the past. However, most of these projects have focused on advanced disease. Thus, genetic alterations that influence the behaviour of early-stage tumours have not been fully explored, and we still have much to learn. Consequently, with my project I have analysed a large collection of 524 tumours, the first large comprehensive study on primary melanomas. Therefore, my work could help us understand how cancers evolve and are regulated in their earliest stages.
With my project, I present the architecture of primary melanomas where most tumours are bursting with mutations, often associated with sun damage as a result of sun exposure. I confirmed and presented new candidate genes potentially important in driving melanoma. I also describe additional genes which could have critical roles in central biological pathways responsible for promoting tumour development.
As an example, most melanomas have an activating BRAF mutation, an alteration that promotes tumour growth. I found that a proportion of melanomas could rely on alternative switches, activating the same biological pathway through mutations in EGFR instead of BRAF. These patients might therefore benefit from existing EGFR inhibitor treatments. A second example proposes a role of PRDM2 in cell-cycle regulation, linking to CDKN2A, an important melanoma tumour suppressor gene and a chief component in controlling tumour development.
When tumours progress, they might develop dependencies on particular genes or pathways in order to survive. In my project, I identified such a dependency, where some melanomas harbour amplifications of the IRF4 gene. Subsequently, when the expression of this gene is lost, these tumours cannot survive. Thus, my results suggest that a subset of melanomas would be sensitive to drugs that block expression of this gene.
My outcomes also suggest that an abundance of genetic alterations, known to be associated with a favourable immunotherapy response, do not in fact have a significant survival benefit for patients not receiving immunotherapy. I therefore conclude that an active immune system is required to combat cancer, emphasising the impact of immunotherapy drugs in the treatment of melanoma.
In my second project, I sought to explore the potential of using our immune system to fight cancer. Checkpoint inhibitors, including anti-PD1 and anti-PD-L1 therapies, have revolutionised melanoma care, yet only a minority of patients respond to these treatments. Our comprehension of how PD-L1 expression on melanoma cells is regulated is still limited. By improving our understanding of these processes, we can envision tumour counteractive mechanisms as well as strive to identify new drug targets.
I employed a genome-wide CRISPR-Cas9 screening approach and identified several pathways encompassing the “life cycle of PD-L1”. A second extensive screen validate these findings in eight cancer cell lines of melanoma, bladder and lung cancer origin, and link novel candidate genes to the control of PD-L1 tumour expression. With these results, we learnt that the expression levels of PD-L1 on the surface of tumour cells are carefully monitored through central processes including TAF transcriptional regulators, N-linked glycosylation mediated by an array of ALG proteins and the OST complex, as well as intracellular transport processes governed by TRAPP, COG and HOPS complexes. In addition, my results also suggest a role for epigenetic and cell-cycle regulators in controlling PD-L1 expression, highlighting possible new drug combinations that could be explored in melanoma. Regulation through SPNS1 was also a major finding, providing a novel therapeutic approach by simultaneously targeting PD-L1 expression as well as autophagic processes.
In conclusion, I hope that the knowledge gained through the results of my project will further our comprehension of melanoma progression and diversity, as well as bringing forth novel insights and possible treatment modalities.
Currently in preparation…