Title: Core-Defining lymphatic-stroma interactions in the developing tumour microenvironment
Funder: Medical Research Council

Abstract: There is much excitement about exploiting our immune system to fight cancer instead of more conventional cytotoxic drugs. While successful in vitro, transition to the clinic is proving more difficult. These problems likely arise because tumours create a protective microenvironment, to which our immune system is ineffective. Non-cancerous cells in the tumour form a supportive network known as the tumour stroma. We do not yet fully understand how the stroma promotes tumour development, or how it contributes to the related immune dysfunction. Lymphatics within the stroma drain fluid and proteins from the tumour, while acting as a highway for spreading tumour cells, but they also connect the tumour to our immune system. Therefore, the question arises as to how, although connected to our defences, can a tumour evade immune destruction? Recent evidence suggests that some cancers develop a stroma with features common to the specialized stroma of the lymph node (where immune system decisions are made) and may help silence the anti-tumour immune response. This "lymph node (LN)-like" stroma also shares characteristics with lymphatics. These overlaps point to an intimate relationship between lymphatics and stroma in the establishment of the tumour microenvironment. We hypothesize that rather than simply providing structural support to a developing tumour, the LN-like stroma is a major factor contributing to immunological tolerance and tumour progression, and that the dynamic biophysical and biochemical environment created by lymphatic drainage function is integral to the formation of this stroma. Specifically, these interactions culminate with a stroma capable of a) posing as a chemokine source in response to physical cues, b) sequestering chemokines and cytokines at the tumour, c) restricting particulates/dead cells to the tumour zone, masking them from the immune system, and d) directly presenting tumour-associated antigens to immune cells within the tumour. To evaluate our hypotheses we combine in vivo tumour models and 3D, tissue-engineered in-vitro systems that mimic the biophysical tumour-stroma-lymphatic microenvironment. Such complex in vitro models permit us to explore the interplay between interstitial flow and LN-like stroma; specifically, to determine to what extent direct cell contacts and interstitial flow (alone, or in combination with tumour derived factors) influence stromal phenotype and function. In vitro, however, we cannot account for host responses and so turn to in vivo models. We will employ genetic mouse models including lymphatic deficient mice to determine how the absence of lymphatic drainage impacts LN-like stroma development and how later restoration of the lymphatic network affects tumour fate. Similar models, and in vivo tracer studies will provide insight into the capacity of LN-like stromal cells to behave like their LN relations and control immunological fate of the developing tumour either by direct presentation of antigen or “molecular sieve” function. Stromal cells can be isolated from tumours and ex vivo assays determine their capacity to present antigen. These projects will give vital new insight into how tumour-associated stroma supports skin cancer development, but will have the broader implications of identifying a potential alternative therapeutic target - the tumour stroma.


Research activity codes: 4.1 DISCOVERY AND PRECLINICAL TESTING OF MARKERS AND TECHNOLOGIES;2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS