ESR09 – Shamik Mitra – based in Lund

Project Title: Establishing the clinical relevance of gene expression phenotypes identified in melanomas
PhD Award Expected: Summer 2020

I am a Marie Curie ESR fellow in Melanoma Genomics under Prof. Dr. Göran Jönsson at Lund University, Sweden. A bioinformatician by training, my research interest lies in the field of data science and its application to solve clinical research problems. I am particularly interested about investigating links between genetic and epigenetic modifications associated with cancer.

My bachelor studies in Biomedical Engineering familiarised me with the impact of medical science and technology on daily life. At postgraduate level, I wanted to go deep into the cellular and molecular level understanding of clinical research problems from computational perspective. My postgraduate studies in Bioinformatics (a one year diploma and a subsequent master’s programme) have provided me the suitable platform for that.

Apart from my academic activities, I enjoy reading both International and Indian literature (Franz Kafka to Dan Brown, whichever I can get hold of!). Poetry has been a long time love for me, especially poems of John Keats. And last but not the least, I am a gourmet and always try to experiment with dishes from different cuisines!


Research Summary

Cancer is probably one of the oldest known diseases to humanity, however it is nothing more than an umbrella term for a group of diseases that are as diverse as countries inside a continent.

Malignant melanoma is a type of cancer which arises from a group of pigment producing cells in our body known as melanocytes. Majority of melanomas are attributed to skin and termed as cutaneous melanoma, nevertheless melanomas can occur in other unrelated organs such as eye and digestive system [1,2].

My PhD project as ESR 9, focused on understanding the molecular diversity that exists within the cutaneous melanoma and how such information can be utilized to select patients for different available treatment options. Now, when we imagine a tumor, we think of it as a cluster of malignant cells. However, tumors in reality consists different other types of cells and these cells contribute to the responsiveness and aggressiveness of the tumor itself. Thus, when deciding on the treatment for a particular melanoma tumor, it will be important to know which other types of non-cancerous cells are present there and how they assist or oppose a particular type of therapy. In my research, I primarily aimed to understand the roles of different immune cells present inside melanoma tumors and how such presence translates into better prognosis for the patients.

Figure 1: Combination of mutational and predicted neo- antigen load with immune system activation, associate with better treatment benefit. Adapted from Lauss et al. 2015 [3]

In the first project of my PhD [3], I worked alongside other researchers from our lab and our international collaborators to identify suitable markers for response to adoptive T-cell therapy (ACT). ACT is one of the newer innovative treatments for advanced-stage cancer patients, where patient’s own immune cells are energized externally to fight the tumor. We observed that having more mutations in the tumor not only translates into clinical benefit from the treatment but also prolongs the patient’s survival (Figure 1A). Similarly, it was noticed that tumor’s ability to generate neoantigens which are protein fragments that likely elicit a response from the immune system, associated strongly with treatment benefit and patient survival (Figure 1B). Additionally, we observed the enrichment of immune system associated genes in the tumors of patients who benefited from the therapy (Figure 1C). Overall, we can speculate that a combination of patient tumor mutational and neoantigen count/load along with the immune enrichment would be a good marker for patient selection in ACT.

Figure 2: Distinct immune-methylation clusters reflect the immune-enrichment in metastatic melanoma tumours and associate with the patient survival

In another project where I worked as a main researcher, we sought to explore how different immune cells enrich in the metastatic melanoma tumors and their association with patient prognosis. Using a major epigenetic modification known as DNA methylation (modification without altering the genomic units of DNA), metastatic melanoma tumors were grouped into 3 distinct clusters based on their immune-methylation characteristics (Figure 2A). Using other metastatic melanoma datasets, these clusters were further validated (Figure 2B) and they reported a statistically significant association with the melanoma-specific survival for the patients (Figure 2C). Overall, we can suggest that these immune-methylation clusters hint at a consensus in the immune enrichment of melanoma tumors and might offer useful guidance to therapies.

Treating melanoma has found new directions in the 21st century with emergence of new innovative therapies, such as immunotherapies and targeted treatments. More and more we are being able to treat advanced-stage patients, which was not possible earlier. I hope that our research shall help significantly to uncover the hidden faces of melanoma and shall broaden the horizon of current therapies.

  1. Simons M, Ferreira J, Meunier R, et al: Primary versus Metastatic Gastrointestinal Melanoma: A Rare Case and Review of Current Literature. Case Rep Gastrointest Med 2016:2306180, 2016
  2. Kaliki S, Shields CL: Uveal melanoma: relatively rare but deadly cancer. Eye 31:241-257, 2017
  3. Lauss M, Donia M, Harbst K, et al: Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nature Communications 8:1738, 2017

Publications

Lauss M, Donia M, Harbst K, Andersen R, Mitra S, Rosengren F, Salim M, Vallon-Christersson J, Törngren T, Kvist A, Ringnér M, Svane IM, Jönsson G. Mutational and putative neoantigen load predict clinical benefit of adoptive T cell therapy in melanoma. Nat Commun. 2017 Nov 23;8(1):1738. Available at: https://www.nature.com/articles/s41467-017-01460-0

Betancourt* LH, Pawlowski* K, Eriksson* J, A. Szasz* M, Mitra S, Pla I, Welinder C, Ekedahl H, Broberg P, Appelqvist R, Yakovleva M, Sugihara Y, Miharada K, Ingvar C, Lundgren L, Baldetorp B, Olsson H, Rezeli M, Wieslander E, Horvatovich P, Malm J, Jönsson G, Marko-Varga G. Improved survival prognostication of node-positive malignant melanoma patients utilizing shotgun proteomics guided by histopathological characterization and genomic data. Sci Rep. 2019 Mar 26;9(1):5154. * Equal contribution. Available at: https://www.nature.com/articles/s41598-019-41625-z

Sanna A, Harbst K, Johansson I, Christensen G, Lauss M, Mitra S, Rosengren F, Häkkinen J, Vallon-Christersson J, Olsson H, Ingvar Å, Isaksson K, Ingvar C, Nielsen K, Jönsson G. Tumour genetic heterogeneity analysis of chronic sun-damaged melanoma. Pigment Cell Melanoma Res. 2019 Dec 7. Available at: https://onlinelibrary.wiley.com/doi/full/10.1111/pcmr.12851

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