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The molecular mechanisms underlying the tumour-determined immune cell infiltrate in oral squamous cell carcinoma


Institute of Dentistry

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Dr M T Teh , Dr A Biddle No more applications being accepted Competition Funded PhD Project (European/UK Students Only)

About the Project

Background and significance:
Oral squamous cell carcinoma (OSCC) is one of the top ten cancers worldwide, with over 300,000 cases annually, and incidence is increasing both worldwide and in the UK (in the UK, incidence has increased by 23% over the past decade). The majority of cases are HPV-negative. HPV-negative OSCC is a deadly disease with frequent metastatic spread, which is the single most important predictor of outcome (1). It is also exceptionally amenable to in vitro experimental modelling of human tumour behaviour. This is due to the excellent recapitulation of in vivo tumour heterogeneity by established OSCC cell lines (2, 3).

Tumours are infiltrated by an array of different cell types that interact with the tumour and greatly influence tumour behaviour and disease course (4). In HPV-negative OSCC, an important category of tumour infiltrating cells is the immune cell infiltrate, which contains an abundance of macrophages and T-cells (5). The makeup of the immune cell infiltrate has a marked impact on clinical outcome (6). Tumour infiltrating T-cells are a particular indicator of favourable prognosis in OSCC (7), whereas tumour associated macrophages (TAMs) are an indicator of poor prognosis (8). TAMs act to suppress T-cells, and therefore the makeup of the immune cell infiltrate has a major bearing on the response to immunotherapy techniques that seek to enhance the T-cell response to the tumour (9, 10). The makeup of the immune cell infiltrate is controlled by factors released by the tumour, and in this way each tumour determines its own immune cell infiltrate (9, 11). This raises the prospect that genetic and cellular profiling of the tumour may enable prediction of the immune cell infiltrate and thus selection of the best immunotherapeutic approach for the patient.

Cancer stem cells (CSCs), the sub-population of tumour cells that possess tumour-initiating potential (12, 13), adopt phenotypes that drive tumour invasion and metastasis (14, 15) and express heightened resistance to therapy (2, 16). These cells are therefore of particular importance to tumour progression, and present a promising target for development of drugs that can stop metastasis. We have recently modelled the central role of CSCs in progression of OSCC (3, 14). In animal models of SCC, it has now been shown that CSCs interact with the immune infiltrate in order to create a permissive microenvironment that sustains their CSC phenotype and promotes tumour progression (17). This work now needs to be brought into a clinically relevant human OSCC model; understanding these interactions in human tumours may enable development of immunotherapeutic approaches that halt tumour progression by targeting the interactions between immune cells and CSCs.

Hypothesis and aims:
We hypothesise that the mutational profile of the tumour generates heterogeneity between patients in tumour-immune interactions, which are mediated by CSCs. This plays an important role in determining the cellular profile of the immune infiltrate in OSCC, which influences tumour progression.

We propose to test this hypothesis through the following aims:
(a) Characterise the genetic drivers and the immune infiltrate in a retrospective cohort of FFPE OSCC specimens stratified by pathological prognosis, identifying associations between genetic drivers, immune components, and prognosis.
(b) Test heterocellular interactions between defined tumour and immune cell populations in a tumour-on-a-chip device.
(c) Assess the role of CSCs in mediating these interactions, and identify the key signalling molecules. Determine how these signalling molecules contribute mechanistically to the maintenance of CSCs and formation of the immune cell infiltrate.

Environment and supervision:
This project will benefit from the state of the art facilities of the Blizard Institute, which have been created and funded to support cutting-edge multi-disciplinary research (www.qmul.ac.uk/blizard/research/core-facilities/). We have assembled an experienced multi-disciplinary team to manage this project. The project will be led by two OSCC experts (Dr Adrian Biddle, Blizard Institute; Dr Muy-Teck Teh, Institute of Dentistry) (2, 3, 14, 19, 20) and a head and neck pathologist (Dr Hannah Cottom, Barts Health) (3, 21, 22).

How to apply
To apply, please click the 'institution website' button.

The successful candidate must be a registered dental clinician in the UK.

Funding Notes

These studentships will fund a student with a clinical qualification and GMC / GDC registration at any career stage below consultant. They will be funded for three years at current, MRC rates. Studentships will include PhD fees (at home/EU levels) and up to £6000 pa for consumables. Further consumables / funding for travel may be available on application.

References

1. Sano D, Myers JN. Metastasis of squamous cell carcinoma of the oral tongue. Cancer metastasis reviews. 2007;26(3-4):645-62.
2. Biddle A, Gammon L, Liang X, Costea DE, Mackenzie IC. Phenotypic Plasticity Determines Cancer Stem Cell Therapeutic Resistance in Oral Squamous Cell Carcinoma. EBioMedicine. 2016;4:138-45.
3. Youssef G, Gammon L, Ambler L, Wicker B, Patel S, Cottom H, et al., Biddle A. Disseminating cells in human tumours acquire an EMT stem cell state that is predictive of metastasis. bioRxiv. 2020:2020.04.07.029009.
4. Balkwill FR, Capasso M, Hagemann T. The tumor microenvironment at a glance. Journal of cell science. 2012;125(Pt 23):5591-6.
5. Puram SV, Tirosh I, Parikh AS, Patel AP, Yizhak K, Gillespie S, et al. Single-Cell Transcriptomic Analysis of Primary and Metastatic Tumor Ecosystems in Head and Neck Cancer. Cell. 2017;171(7):1611-24 e24.
6. Gentles AJ, Newman AM, Liu CL, Bratman SV, Feng W, Kim D, et al. The prognostic landscape of genes and infiltrating immune cells across human cancers. Nat Med. 2015;21(8):938-45.
7. de Ruiter EJ, Ooft ML, Devriese LA, Willems SM. The prognostic role of tumor infiltrating T-lymphocytes in squamous cell carcinoma of the head and neck: A systematic review and meta-analysis. OncoImmunology. 2017;6(11):e1356148.
8. Kumar AT, Knops A, Swendseid B, Martinez-Outschoom U, Harshyne L, Philp N, et al. Prognostic Significance of Tumor-Associated Macrophage Content in Head and Neck Squamous Cell Carcinoma: A Meta-Analysis. Frontiers in oncology. 2019;9(656).
9. DeNardo DG, Ruffell B. Macrophages as regulators of tumour immunity and immunotherapy. Nature Reviews Immunology. 2019;19(6):369-82.
10. Economopoulou P, Perisanidis C, Giotakis EI, Psyrri A. The emerging role of immunotherapy in head and neck squamous cell carcinoma (HNSCC): anti-tumor immunity and clinical applications. Annals of Translational Medicine. 2016;4(9):13.
11. Li J, Byrne KT, Yan F, Yamazoe T, Chen Z, Baslan T, et al. Tumor Cell-Intrinsic Factors Underlie Heterogeneity of Immune Cell Infiltration and Response to Immunotherapy. Immunity. 2018;49(1):178-93.e7.
12. Clarke MF, Dick JE, Dirks PB, Eaves CJ, Jamieson CH, Jones DL, et al. Cancer stem cells--perspectives on current status and future directions: AACR Workshop on cancer stem cells. Cancer Res. 2006;66(19):9339-44.
13. Driessens G, Beck B, Caauwe A, Simons BD, Blanpain C. Defining the mode of tumour growth by clonal analysis. Nature. 2012;488(7412):527-30.
14. Biddle A, Liang X, Gammon L, Fazil B, Harper LJ, Emich H, et al. Cancer stem cells in squamous cell carcinoma switch between two distinct phenotypes that are preferentially migratory or proliferative. Cancer Res. 2011;71(15):5317-26.
15. Lawson DA, Bhakta NR, Kessenbrock K, Prummel KD, Yu Y, Takai K, et al. Single-cell analysis reveals a stem-cell program in human metastatic breast cancer cells. Nature. 2015;526(7571):131-5.
16. Kreso A, O'Brien CA, van Galen P, Gan OI, Notta F, Brown AM, et al. Variable clonal repopulation dynamics influence chemotherapy response in colorectal cancer. Science. 2013;339(6119):543-8.
17. Taniguchi S, Elhance A, Van Duzer A, Kumar S, Leitenberger JJ, Oshimori N. Tumor-initiating cells establish an IL-33-TGF-beta niche signaling loop to promote cancer progression. Science. 2020;369(6501).
18. Leemans CR, Snijders PJF, Brakenhoff RH. The molecular landscape of head and neck cancer. Nature Reviews Cancer. 2018;18(5):269-82.
19. Qadir F, Aziz MA, Sari CP, Ma H, Dai H, Wang X, et al., Teh MT. Transcriptome reprogramming by cancer exosomes: identification of novel molecular targets in matrix and immune modulation. Mol Cancer. 2018;17(1):97.
20. Teh MT, Hutchison IL, Costea DE, Neppelberg E, Liavaag PG, Purdie K, et al. Exploiting FOXM1-orchestrated molecular network for early squamous cell carcinoma diagnosis and prognosis. Int J Cancer. 2013;132(9):2095-106.
21. Cottom H, Mighell AJ, High A, Bateman AC. Are plasma cell-rich inflammatory conditions of the oral mucosa manifestations of IgG4-related disease? J Clin Pathol. 2015;68(10):802-7.
22. Barry P, Vatsiou A, Spiteri I, Nichol D, Cresswell GD, Acar A, Cottom H, et al. The Spatiotemporal Evolution of Lymph Node Spread in Early Breast Cancer. Clin Cancer Res. 2018;24(19):4763-70.
23. McCarthy NE, Eberl M. Human γδ T-Cell Control of Mucosal Immunity and Inflammation. Frontiers in Immunology. 2018;9(985).
24. McCarthy NE, Hedin CR, Sanders TJ, Amon P, Hoti I, Ayada I, et al. Azathioprine therapy selectively ablates human Vδ2+ T cells in Crohn’s disease. The Journal of Clinical Investigation. 2015;125(8):3215-25.
25. Di Cio S, Boggild TML, Connelly J, Sutherland DS, Gautrot JE. Differential integrin expression regulates cell sensing of the matrix nanoscale geometry. Acta Biomater. 2017;50:280-92.
26. Kong D, Peng L, Di Cio S, Novak P, Gautrot JE. Stem Cell Expansion and Fate Decision on Liquid Substrates Are Regulated by Self-Assembled Nanosheets. ACS Nano. 2018;12(9):9206-13.
27. Kim J, Lana B, Torelli S, Ryan D, Catapano F, Ala P, et al. A new patient-derived iPSC model for dystroglycanopathies validates a compound that increases glycosylation of α-dystroglycan. EMBO reports. 2019;20(11):e47967.
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