Exploring unconventional T cells in Merkel cell carcinomas using immunogenomic methods | Dr Richard Tothill

The Rare Disease Ocogenomics group's work on Merkel cell carcinoma has shown the existence of an under studied type of T cell infiltrating these tumours, which likely has prognostic and therapeutic significance for patients with this rare but aggressive type of skin cancer.

Group Lead, Rare Disease Oncogenomics
UMCCR and Department of Clinical Pathology

4 March 2020

Merkel cell carcinoma (MCC) is an aggressive neuroendocrine cancer of the skin. MCC has two aetiologies corresponding to either Merkel cell polyoma virus infection or sun-induced carcinogenesis. Both subtypes are immunogenic and ~50% of MCC show response to immunotherapies.

To understand the immune response in MCC we used a combination of multiplex-immunohistochemistry (m-IHC), flow cytometry and single-cell RNA-sequencing. Remarkably, in 40% of patients more than one-fifth of infiltrating T cells MCC lacked expression of common T cell markers CD4 and CD8 – termed double negative (DN) T cells. Flow cytometry and single-cell genomics showed DN T cells in MCC were mostly gamma delta T cells.

We developed a gene-expression score for gamma delta T cells and applied it to a larger series of MCC showing this had prognostic significance. Gamma delta T cells are therefore likely to be important for immune surveillance in MCC and offer novel avenues for immunotherapy.

Dr Richard Tothill

Dr Richard Tothill received his undergraduate degree with 1st class honours in 1996 at Murdoch University (Perth, WA). He subsequently worked on genomic technology development at Glaxo-Welcome (Genetics Division, UK) before returning to Australia in 2001 to undertake his PhD with Prof David Bowtell (Peter Mac, University of Melbourne) on the development of a microarray-based diagnostic test for cancers of unknown primary. As a post-doctoral researcher in the Bowtell lab he made the seminal discovery of high-grade serous ovarian cancer subtypes using gene-expression profiling (PMID:18698038, cit: 734).

Dr Tothill occupied a brief post-doc position at Baker IDI before returning to Peter Mac to manage the insititute’s genomics core facility while also maintaining primary research output across a number of areas. From 2012 within the laboratories of Prof Ricky Johnstone and Prof Rod Hicks he created genomic research projects on murine models of lymphoma and on rare neuroendocrine cancers, respectively.

In 2017, he became an independent group leader and head of the Rare Disease Oncogenomics Laboratory within the University of Melbourne Department of Clinical Pathology. He also maintains an honorary appointment at the Peter Mac. He is a leader in the field of cancer genomics nationally with a growing international reputation on neuroendocrine cancers and cancers of unknown primary. He has extensive experience in academic research encompassing genomic analyses of solid cancers with an emphasis on genomic pathology, diagnostic development and precision medicine.