skip to primary navigationskip to content
 

Jacqui Shields

j shieldsDr Jacqui Shields

Biography | Pubmed

Group Webpage

 

Stroma Function in the Tumour Microenvironment

The recent successes of immunotherapy platforms to block checkpoints such as CTLA-4 and PD-1, augmenting the immune response represent a major therapeutic advancement. However, current approaches remain effective in just a few cancer types, and many patients still fail to respond. Therefore, Increasing our understanding of anti-tumour immunity and the suppressive networks at play will be fundamental to the development of improved strategies and design of new, targeted therapeutic platforms.

js13a
Please Click for Larger Image
To achieve this we need to consider the tumour as a whole. The tumour microenvironment is a complex, dynamic ecosystem comprising of tumour cells and supportive stromal cells, which together foster tumour development and progression.

The stroma is made up of a heterogeneous collection of cells including the blood and lymphatic endothelial cells, fibroblasts, and immune cells (Figure 1), which support many pro-tumour functions necessary for a tumour to establish and progress. Recently, cancer associated fibroblasts (CAFs), one of the most abundant stromal populations have emerged as potential immune modulators through the secretion of inflammatory mediators that can impact immune cell recruitment and polarization. However, it is unclear if this is the only means by which stromal cells can contribute to immune suppression, how these or other suppressive activities develop, or how they are regulated. To this end, our interests lie with the lymphatic vessels and a subset of fibroblasts that express the glycoprotein podoplanin, found both in tumours and lymph nodes.

In many cancers, the presence of these populations are correlated with poor patient prognosis, yet how their presence translates to outcome is unclear; a first clue came from my early work that demonstrated podoplanin+ CAFs present within tumours coincided with a switch in immune populations present (Science 2010) implicating them as potential immune regulators. From these observations, my lab has set out to explore the mechanisms and evolution of stromal-mediated immune dysfunction in the tumour microenvironment with the ultimate goal to identify novel therapeutic targets.

To achieve these goals, we take a multidisciplinary approach, integrating experimental cancer models, complex in vitro and in silico systems, high throughput genomics and bioinformatics. Specifically we are investigating:

 

Mechanisms of stromal-mediated immune dysfunction at the primary tumour:
We have developed complex in vitro co- and triple-culture systems (pictured), which we combine with 4D imaging, functional immunology-based assays to unravel the contributions of CAFs towards antigen specific T cell dysfunction within tumours. Our findings are then verified in complementary preclinical models.

 

How stromal cells operate in tumour draining lymph nodes

The tumour microenvironment also extends to lymph nodes that are connected via lymphatic vessels, and collect all components exiting the tumour microenvironment.  We are investigating how the stromal compartments here can be controlled remotely from the tumour to promote a “tumour-friendly” environment. To do this we combine–omics and in silico technologies with preclinical tumour models.

Text Box: Image 4

Development of novel therapeutic strategies to target stroma
Our ultimate goal is to exploit the data obtained through our research towards new or improved therapies. We take a highly collaborative approach with academics, engineers and biotech to make steps towards this.

 

Contact:

Click here to contact Dr Jacqui Shields by email.

 

Recent Publications:

Rapid sentinel lymph node diagnosis using carboxydextran-coated superparamagnetic iron nanoparticle without long-term immune functional implications. Luisa Pedro, Quentin Harmer, Eric Mayes, Jacqueline D. Shields, 2019:  . Advanced Online Publication, April 15. Small.

Single cell transcriptomics of regulatory T cells reveals trajectories of tissue adaptation. Ricardo Miragaia, Tomás Gomes, Agnieszka Chomka,  Laura Jardine,  Angela Riedel,  Ahmed N Hegazy, Ida  Lindeman,  Guy Emerton,  Thomas Krausgruber,  Jacqueline ShieldsMuzlifah Haniffa,  Fiona Powrie,  Sarah A Teichmann 2019.  5 Feb. Immunity. 

Role of stromal osmoregulation in cellular transformation in cancer and disease. David Shorthouse, Angela Riedel, Emma Kerr, Luisa Pedro, Dora Bihary, Shamith Samarajiwa, Carla Martins, Jacqueline Shields*, Benjamin A Hall1* , 2018. 9(1):3011. Nature Communications.

Tumour-associated macrophages exploit an innate wound healing response to facilitate metastasis. Tamara Muliaditan, Mary Okesola, Jonathan Caron, Mirella Georgouli, Peter Gordon, Sharanpreet Lall, Desislava Kuzeva, Luisa Pedro, Jacqueline D. Shields, Cheryl E. Gillett, Sandra S. Diebold, Victoria Sanz-Moreno, Tony Ng, Esther Hoste, and James N. Arnold, 2018. 9(1):2951. Nature Communications.

Cancer-associated Fibroblasts Provide Immune Protection to Tumour Cells via Antigen-Specific Deletion of CD8+ Cytotoxic T Cells. M Lakins, E Ghorani, H Munir, C Martins, JD Shields, 2018.  9: 948.  Nature Communications.

Tumor-induced stromal reprogramming drives lymph node transformation. Riedel A, Shorthouse D, Haas L, Hall BA, Shields J. . 2016 Jul 11. doi: 10.1038/ni.3492. Nat Immunol

Lymphatics: at the interface of immunity, tolerance and tumour metastasis. Shields JD.  2011 Oct;18(7):517-31. Microcirculation.

Induction of lymphoidlike stroma and immune escape by tumors that express the chemokine CCL21. Shields JD, Kourtis IC, Tomei AA, Roberts JM, Swartz MA. 2010 May 7;328(5979):749-52. Science

Vascular endothelial growth factor-C and C-C chemokine receptor 7 in tumor cell-lymphatic cross-talk promote invasive phenotype. Issa A, Le TX, Shoushtari AN, Shields JD, Swartz MA.  2009 Jan 1;69(1):349-57. Cancer Res.

Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Shields JD, Fleury ME, Yong C, Tomei AA, Randolph GJ, Swartz MA.  2007 Jun;11(6):526-38. Cancer Cell.