Do differences in tumour microenvironment and immune response in peripheral blood predict melanoma relapse?

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This is one of two research projects advancing the study of melanoma. The University of Melbourne is the home institution for this project. To view the Manchester-based partner project, click here.

Melanoma is the most aggressive type of skin cancer with over 3000 deaths annually in the UK and Australia combined. Management of resected early-stage melanoma where there is no spread beyond the skin remains a challenge. Standard pathological characteristics to determine risk include melanoma thickness and ulceration. However, a very small proportion of thin (stage I) melanomas can also develop distant spread. It is critical to understand better why some melanomas go on to metastasise, whilst others are cured by surgery alone. In addition, biomarkers are needed to predict which patients will be cured versus those requiring additional monitoring or (neo)adjuvant therapy. In the DETECTION trial (Circulating tumour DNA guidEd Therapy for stage IIB/C mElanoma after surgiCal resection) we are monitoring for molecular relapse using ctDNA in 1050 patients. However, patients with thin melanomas are currently not included due to the challenge of balancing the benefits of additional monitoring with potential anxiety associated with testing such a low-risk population.

To better identify patients at high relapse risk, the tumour microenvironment and immune response to cancer will be assessed. Firstly, the student will examine features of primary melanoma predicting recurrence. Initially, they will focus on low-risk thin melanomas (Stage I-IIA) to identify patients who would potentially benefit from additional monitoring. Techniques developed during this project will then be applied to understanding which patients with thicker (Stage IIB/C) recruited to the DETECTION study are likely to relapse. Secondly, the student will examine whether immune monitoring through characterising T cell receptor (TCR) clonality and diversity in the tumour microenvironment and blood provides information regarding the kinetics of immune escape.

Detailed characterisation of interactions between cancer, the immune system and stroma in primary melanoma contributes to the understanding of mechanisms of progression. Previous research showed topological primary tumour graphs can provide information regarding tumour/stroma/immune interactions associated with prognosis. However, this work was based on hematoxylin and eosin specimens, therefore it was not possible to fully characterise subsets of cells. This project will use ultra-high multiplexed imaging, enabling a deeper understanding of cell types and spatial relationships within the primary melanoma microenvironment.

Tumour infiltrating lymphocytes in melanoma include T cells of diverse differentiation states each having a distinct function. A subset of these T cells are truly tumour responsive, and the remainder is bystander T cells trafficking into the tumour in response to interferon-induced chemokines. Tumour enriched clones (TEC) are T cell clones that are dominant (>1%) in the tumour, which can traffic into the tumour from the draining lymph node or peripheral blood (PB). Multiple studies have reported that TEC clonality and changes to the overall diversity can provide an early biomarker of response to immune therapy in melanoma. Immune escape is associated with melanoma clonal evolution, loss of MHC class I expression, and reduced PB TEC clonality. An alternate mechanism includes exhaustion of tumour-responsive T cells. To test the predominant mechanism of immune escape we will examine whether TEC clonality reduces over time in those that relapse or whether it remains stable, suggesting that T cell exhaustion or defective neoantigen presentation are more important.

Project goals

Key questions of this research project are:

  1. Does the spatial composition of melanoma (cancer cell, immune and stromal components) predict the likelihood of relapse?
  2. Is the clonality and diversity of tumour-resident and sentinel lymph node T cells associated with melanoma relapse?
  3. What are the kinetics of T cell clonality in relapsing patients?

This project will provide an in-depth understanding of how features of the tumour microenvironment and immune response contribute to melanoma progression in order to identify novel biomarkers, to better stratify patients for monitoring and future treatments.

Supervision team

*Click on the researcher's name above to learn more about their publication and grant successes.

Who we are looking for

We are seeking a PhD candidate with the following skills:

    • Demonstrated experience in the field of science in microbiology and/or immunology and an interest in quantitative and qualitative research
    • Demonstrated ability to work independently and as part of a team
    • Demonstrated time and project management skills
    • Demonstrated ability to write research reports or other publications to a publishable standard (even if not published to date)
    • Excellent written and oral communication skills.
    • Demonstrated organisational skills, time management and ability to work to priorities.
    • Demonstrated problem-solving abilities.

Further details

The PhD candidate will benefit from the combined expertise of the project supervisors, and the embedding into two research environments.

Throughout her career, Prof Caroline Dive has attracted several prizes and awards, most notably she was awarded the Pasteur-Weizmann/Servier International Prize in 2012, the AstraZeneca Prize for Women in Pharmacology in 2016 and in 2019, the Heine H. Hansen Lectureship Award by the International Association for the Study of Lung Cancer (IASLC). She is a fully elected member of EMBO (2020), an elected Fellow of the Academy of Medical Sciences (2015), Fellow of the British Pharmacological Society (2012) and Fellow of the European Academy of Cancer Sciences (2011).

In 2017, Caroline was awarded Commander of the Order of the British Empire (CBE) for her services to cancer research. Most recently, Caroline was presented with the first Johann Anton Merck Award in 2020 for outstanding preclinical research in oncology and is the EACR President 2020 – 2022. Prof Sarah-Jane Dawson’s research focuses on the development of noninvasive blood-based biomarkers ('liquid biopsies') for clinical application, including early detection, risk stratification and disease monitoring in cancer management.

This PhD project will be based at the University of Manchester with a minimum 12-month stay at the University of Melbourne.

The candidate will be enrolled in the PhD program at the University of Manchester and in the faculty of Medicine, Dentistry and Health Sciences at the University of Melbourne.

To apply for this joint PhD opportunity, and to view the entry requirements, visit How to apply.

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