Mucosal Immunity and Cancer Laboratory

Laboratory overview

The Mucosal Immunity and Cancer Laboratory focuses on the biological pathways that drive immune cell development and function at the body’s surfaces. Our current work investigates specialised immune cell populations of the intestinal mucosa known as intraepithelial lymphocytes, including T cells and innate lymphoid cells. These immune cells interact with the intestinal epithelium which forms a physical barrier to protect us from the external environment, including commensal microbes in our gut, pathogens and food antigens. Ultimately, the mucosal immune cells play a critical role in maintaining intestinal homeostasis and preventing infection. Increasing evidence suggests that these specialised immune cells also play a role in development of cancer.

Modulation of the immune system has revolutionized the treatment of some cancer types and it is now evident that manipulating the immune system is a powerful technique to treat and potentially aid with cancer prevention. Understanding the different functions of immune cells in the intestine and the role they play in tumourigenesis, will pave the way for discovery of new immunotherapies to harness our own immune cells to eradicate tumours. Our work is directly relevant for cancers associated with the gastronintestial tract, for example bowel cancer, but is also applicable to other cancer types that develop at mucosal or barrier surfaces, including the lung and skin.

The human body’s own immune cells have the ability to recognise and kill tumour cells; we are studying new ways of enhancing this potential. Dr Lisa Mielke, Head, Mucosal Immunity and Cancer Laboratory
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Our focus

Function of intestinal immune cells in bowel cancer

Intraepithelial lymphocytes (IELs) are immune cells that continually survey intestinal epithelial cells for infection or damage. Bowel cancer forms when the epithelial cells become damaged and change so as to grow in an uncontrolled manner. The role of IELs in this process, and whether or not they play a role in tumour cell growth or killing tumour cells, has not been studied in detail. Our laboratory aims to understand these molecules, including the function of steady state IEL development-driving transcription factors in the development of cancer.

Regulation of cytokines in the gastrointestinal tract

Cytokines, such as IL-17 and IL-22, are secreted by immune cells and are critical in enhancing epithelial cell and tumour survival in the intestine. Bowel cancer patients with increased IL-17 and IL-22 levels experience increased tumour growth and have a poorer prognosis. We are dissecting the molecular pathways and cell types involved in regulating IL-17 and IL-22 production in order to investigate the role these cytokines play in bowel cancer progression. It is crucial that we understand these mechanisms so that we can develop new immune cell-mediated therapies for the treatment of gastrointestinal cancers.

Influence of the microbiome on immune health  

Each person’s microbiome is unique and is made up of good bacteria, viruses and fungi that live on the body’s surfaces, such as the skin and intestine. Our understanding of these resident microbes and how they affect the body’s immune response to an infectious organism or disease, such as cancer, is limited. We are working to understand the mechanisms that link the microbiome to overall immune cell health, including the activation of transcription factors that guide immune cell development, as well as the cytokines they secrete in order to communicate with the rest of the body's cells.  

Quick Facts

Where are immune cells found?

As well as being found in the blood, immune cells are present in the body’s tissues and they continuously survey them for infection and cancer.

What are mucosal surfaces?

The body’s mucosal surfaces are its mucus-covered tissues; these include the lungs and gastrointestinal tract. These sites are home to specialised immune cells, which play a critical role in maintaining mucosal surfaces in order to protect the body from the external environment.

What is the microbiome?

The microbiome comprises all the bacteria and other microbes that live on the body’s surfaces, such as the skin and intestine. Interaction between these microbes and immune cells is critical in shaping the immune system, and can even influence the body's response to some cancer treatments.

  1. O'Reilly LA**, Putoczki TL**, Mielke LA, Low JT, Lin A, Preaudet A, Herold MJ, Yaprianto K, Tai L, Kueh A, Pacini G, Ferrero RL, Gugasyan R, Hu Y, Christie M, Wilcox S, Grumont R, Griffin MDW, O'Connor L, Smyth GK, Ernst M, Waring P, Gerondakis S, Strasser A. 2018. Loss of NF-kB1 Causes Gastric Cancer with Aberrant Infalmmation and Expression of Immune Checkpoint Regulators in a STAT-1-Dependent Manner.Immunity. 48:570-583.** These authors contributed equally.
  2. Seillet C, Mielke LA, Amann-Zalcenstein DB, Su S, Gao J, Almeida FF, Shi W, Ritchie ME, Naik SH, Huntington ND, Carotta S, Belz GT. 2016. Deciphering the innate lymphoid cell transcriptional program. Cell Reports. 17:436-447.
  3. Delconte RB, Shi W, Sathe P, Ushiki T, Seillet C, Minnich M, Kolesnik TB, Rankin LC, Mielke LA, Zhang JG, Busslinger M, Smyth MJ, Hutchinson DS, Nutt SL, Nicholson SE, Alexander WS, Corcoran LM, Vivier E, Belz GT, Carotta S, Huntington ND. 2016. The helix-loup-helix protein ID2 governs NK cell fate by tuning their sensitivity to IL-15. Immunity 44:103-15.
  4. Mackay LK, Wynne-Jones E, Freestone D, Pellicci DG, Mielke LA, Newman DM, Braun A, Masson F, Kallies A, Belz GT, Carbone FR. 2015. T-Box transcription factors combine with the cytokines TGF-band IL-15 to control Tissue-resident memory T cell fate. Immunity 43:1101-11.
  5. Rankin L.C, M.J Girard-Madoux, C. Seillet , L.A Mielke, Y. Kerdiles, A. Fenis , E. Wieduwild , T. Putoczki, S. Mondot, O. Lantz, D. Demon, A.T Papenfuss, G.K Smyth, M. Lamkanfi, S. Carotta, J.C Renauld, W. Shi, S. Carpentier, T. Soos, C. Arendt, S. Ugolini, N.D Huntington, G.T Belz, E. Vivier. 2016. Complementarity and redundancy of IL-22 producing innate lymphoid cells. Nature Immunology 17:179-86.
  6. Mielke L, A. Preaudet, G. Belz, T. Putoczki. 2015. Confocal laser endomicroscopy to monitor the colonic mucosa of mice. Journal of Immunological Methods. 421:81-8.
  7. Dunne A**, L.A. Mielke**, A. Allen, C.E. Sutton, R. Higgs, S.C. Higgins and K.H.G. Mills. 2014. A novel TLR2 agonist from Bordetella pertussis is a potent adjuvant that promotes protective cellular immunity with an acellular pertussis vaccine. Mucosal Immunology. 8:607-17** These authors contributed equally.
  8. Mielke, L. A., J. R. Groom, L. C. Rankin, C. Seillet, F. Masson, T. Putoczki, and G. T. Belz. 2013. TCF-1 controls ILC2 and NKp46+RORgammat+ innate lymphocyte differentiation and protection in intestinal inflammation. Journal of immunology 191: 4383-4391.
  9. Mielke, L. A., S. A. Jones, M. Raverdeau, R. Higgs, A. Stefanska, J. R. Groom, A. Misiak, L. S. Dungan, C. E. Sutton, G. Streubel, A. P. Bracken, and K. H. Mills. 2013. Retinoic acid expression associates with enhanced IL-22 production by gammadelta T cells and innate lymphoid cells and attenuation of intestinal inflammation. The Journal of experimental medicine 210: 1117-1124.
  10. Seillet C, G.T. Belz and L.A. Mielke. 2014. Complexity of cytokine network regulation of innate lymphoid cells in protective immunity. Cytokine 70:1-10 (Invited review)
  11. Sutton, C. E.**, L. A. Mielke**, and K. H. Mills. 2012. IL-17-producing gammadelta T cells and innate lymphoid cells. European journal of immunology 42: 2221-2231. **Equal contribution.

For a complete list of Lisa Mielke's publications, click here.

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