An investigation into the cellular and molecular mechanisms of how sunlight suppresses anti-tumour immune responses leading to skin cancer development

Summary

Project Significance: Skin cancer is an enormous burden on society causing significant morbidity and mortality. Unfortunately, the incidence of skin cancer continues to rise despite widespread community awareness of the need to protect ourselves from the prime cause of skin cancer; sunlight. The dramatic rise in incidence of melanoma in young women is particularly alarming. The precise reason for this is unknown, but may be attributed to a number of variables including increased solarium use, complacency towards recreational sun exposure, or the desire for a “healthy tan”. Clearly, limiting the amount and type of sun exposure has been insufficient to reduce skin tumour incidence. The cellular and molecular mechanisms of carcinogenesis are complex. To understand it, one needs to appreciate the two facets that make carcinogenesis possible; genetic damage and immune suppression. The ultraviolet (UV) wavelengths in sunlight cause both and so are a complete carcinogen. Indeed, UV is one of the most potent and significant environmental carcinogens humans are exposed to. However, while the DNA damaging properties of UV are well known, the mechanisms underlying UV-immunosuppression are not understood. This project will investigate the mechanisms by which UV suppress anti-tumour immune responses.

Supervisor(s)

Dr Scott Byrne

Research Location

Central Clinical School, Department of Infectious Diseases and Immunology

Program Type

PHD

Synopsis

Project Background: It has previously been shown that exposing mice to UV prior to tumour inoculation causes the tumours to progress. The conclusion was that UV had immune suppressive properties that inhibit the anti-tumour response. We and others have since shown that the mechanism of this suppression is ultimately mediated by regulatory T (T regs) and suppressor B cells (1,2). The mechanisms of how suppressor B cells are activated after exposure to UV will be studied in this project.

Mast cells are bone marrow derived cells that circulate in the blood as immature progenitors. They migrate into peripheral tissues where they differentiate into mature, long-lived mast cells. Here they release inflammatory mediators in response to cross-linking of their IgE receptors and as such have traditionally been associated with allergic type inflammation. However, increasing evidence suggests mast cells also have important immunoregulatory functions. Indeed, mast cells are critical to the ability of UV to suppress immune responses (3). We recently showed that the mechanism of mast cell-mediated immunosuppression is via UV-induced mast cell migration from the skin to the draining lymph nodes (4). This migration was dependent on the CXCR4-CXCL12 chemokine pathway as CXCL12 was significantly up-regulated in the nodes and CXCR4+ mast cells were blocked from migrating in vivo in the presence of the CXCR4 inhibitor AMD3100. Blocking mast cell migration also prevented UV-immunosuppression (4). Hence mast cell migration to lymph nodes in response to UV is required for suppression of immune responses. The importance of this mast cell migration to the development of skin tumours will be studied in this project.

Finally, in vitro evidence shows that mast cells can activate B cells (5) & our preliminary data suggests that this is a possible mechanism in the generation of suppressor B cells following UV in vivo. Therefore, the final part of this project will investigate whether UV-suppressor B cells are activated by mast cells and if so to determine the molecular mechanisms

References:

1. Byrne, SN and Halliday, GM. B Cells Activated in Lymph Nodes in Response to Ultraviolet Irradiation or by Interleukin-10 Inhibit Dendritic Cell Induction of Immunity. J Invest Dermatol 124(3) p570-578 (2005).

2. Matsumura, Y, Byrne, SN, Nghiem, D, Miyahara, Y and Ullrich, SE. A role for inflammatory mediators in the induction of immunoregulatory B cells. J Immunol 177(7) p4810-4817 (2006).

3. Hart, PH, Grimbaldeston, MA, Swift, GJ, Jaksic, A, Noonan, FP and Finlayjones, JJ. Dermal Mast Cells Determine Susceptibility to Ultraviolet B-Induced Systemic Suppression of Contact Hypersensitivity Responses in Mice. Journal of Experimental Medicine 187(12) p2045-2053 (1998).

4. Byrne, SN, Limon-Flores, AY and Ullrich, SE. Mast cell migration from the skin to the draining lymph nodes upon UV-irradiation represents a key step in the induction of immune suppression. J Immunol 180(7) p4648-4655 (2008).

5. Gauchat, JF et al. Induction of human IgE synthesis in B cells by mast cells and basophils. Nature 365(6444) p340-3 (1993).

Additional Information

PhD Candidate requirements:

Essential criteria:
1.    Science degree with honours (or equivalent)
2.    Scholarship, stipend (or equivalent private funding)*
3.    An enthusiasm for research and discovery
4.    The ability to work in a team
5.    Good written and oral communication skills
* please note: research related activities (e.g. laboratory reagents) will be supplied

Desirable criteria:
1.    1st class honours degree
2.    Animal handling experience
3.    Experience in the processing and/or preparation of tissue for analysis by:
•    Flow cytometry
•    Microscopy

For more information about Dr Byrne’s research please visit:

http://www.infectiousdiseasesandimmunology.med.usyd.edu.au/Scott_Byrne.html

For the University of Sydney’s postgraduate application form:

The course name is: PhD
The course code is: KB000
The CRICOS code is: 006455J

Keywords

Tumour immunology, Skin Cancer, Sunlight, Ultraviolet Radiation, Immune Suppression, immune regulation, Regulatory cells, mast cells, Suppressor B cells, Skin Tumours, Immunology, Chemokines, cell migration, cytokines, Carcinogenesis, B lymphocytes

Opportunity ID

The opportunity ID for this research opportunity is: 857