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Lunch Talk: Stromal Function in the Evolving Tumour Microenvironment: A Role in Immune Modulation?
23. May 2018 @ 11:00 - 13:00
“Stromal Function in the Evolving Tumour Microenvironment: A Role in Immune Modulation?”, Dr. Jacqueline Shields, University of Cambridge, United Kingdom
Speaker: Jacqueline Shields, University of Cambridge, United Kingdom
Host: Postdoc Network DKFZ
Outline of the talk
The recent success of immunotherapy platforms to harness and reactivate the immune response represent a major therapeutic advancement, however, many patients still fail to respond or do not see lasting benefits.
While tumours frequently contain immune infiltrates, our immune system is often unable to mount an effective anti-tumour response, and rather than clearing the lesion, immune populations may promote disease progression and metastasis. Despite these observations, the mechanisms employed by a growing tumour to avoid immune destruction remain unclear, thus increasing our understanding of anti-tumour immunity and the suppressive networks at play during malignant transition will be fundamental to the development of improved strategies and design of new, targeted therapeutic platforms.
Recent evidence indicates that non-cancerous support cells within tumours, referred to as the stroma are emerging as key sources of tumour-promoting inflammation, but little is known how or when in tumour evolution these functions are acquired.
We take a multidisciplinary approach to explore the mechanisms and evolution of stromal-mediated immune dysfunction in the tumour microenvironment and uncouple the immunoregulatory systems governing their suppressive function. As part of this global aim we have demonstrated that one of the most abundant stromal populations, the cancer associated fibroblasts (CAFs), can sample and present tumour antigen to T cells in an antigen specific-antigen dependent manner resulting in T cell deletion. CAFs also stimulate recruitment of neutrophils and neutrophil extracellular trap formation.
Moreover, we have shown that lymph nodes draining a tumour (TDLNs) form part of the extended tumour microenvironment, adapting to tumour-derived signals. LN stromal cells, particularly fibroblastic reticular cells (FRCs), which provide critical structural support and regulate immunity and transport properties of LNs, expand prior to the onset of metastasis and undergo significant remodelling. Profiling of populations from individual resting or TDLNs revealed significant transcriptional alterations in these cells. Of major interest was the observation of downregulated CCL21 and IL-7, two key guidance and T cell survival cues. Coincident with this, altered immune cell composition aberrant immune localization were detected.
In summary, we now beginning to obtain insight into the complexities of stromal interactions that support immune dysfunction as tumours develop, both via direct and indirect mechanisms by multiple players and at multiple sites.