Title: Leukocyte Dynamics
Funder: Cancer Research UK

Abstract: The immune system has been implicated in almost every stage of cancer development, from initiation and growth to recurrence, invasion and metastasis. The role of immunity in cancer is complicated as immune cells can kill cancer cells and stabilise the primary tumour to help prevent spread but they can also produce factors that suppress anti-cancer immunity and benefit tumour growth and dissemination. The immune compartment of cancer is composed of the resident immune cells of the tissue and leukocytes that infiltrate from the circulation. The development of the cancer immune environment is inherently dynamic, and the processes that regulate immune cell recruitment and function are not well understood. Recent success in directing and strengthening the immune system’s anti-cancer functions (e.g. tumour infiltrating lymphocyte (TIL) therapy and immune checkpoint inhibition) highlight the potential for new therapies that can come from a better understanding of how leukocytes are (dys) regulated. However, these strategies do not work for all cancers or all patients. Specialised vasculature and leukocyte dynamics Our group has a particular interest in the lung, both as a site of primary tumour development and as a target of metastasis. The extensive capillary network of the lung is unusual in several ways. Alveolar capillaries are of exceptionally small diameter (~5μm) and are in such close proximity to external mucosa that they share a basement membrane with the epithelium. In contrast to other organs, pulmonary capillaries are thought to be a major site of leukocyte extravasation, with markedly different mechanisms to the general paradigm of leukocyte recruitment. Moreover, localisation and regulation of leukocytes within the pulmonary capillaries is not fully described or well understood. The work of several groups has suggested that neutrophils are important in onco-immunology, and a high neutrophil-to-lymphocyte ratio is associated with poorer prognosis in many advanced cancers. Neutrophils also pose the first-line of defence against many pathogens and play a key role in initiating the host immune response to infection. In addition to potent effector mechanisms, including phagocytosis, degranulation and the recently described process of NETosis, neutrophils can contribute to the inflammatory milieu in a number of ways. Neutrophils can produce and consume chemokines, cytokines and growth factors and can modify the extracellular matrix (which also produces and modulates matrikines – chemoactive products of matrix degradation). Additionally, the accumulation of apoptotic neutrophils and their subsequent clearance is thought to directly contribute to anti-inflammatory programmes at the end of acute inflammatory responses. Taken together, these features mean neutrophils have the potential to contribute to both tumour antagonism and tumour-promoting inflammation, and recent work has demonstrated that neutrophils actually benefit cancer spread in the process of lung metastasis. Because of this diversity of actions and importance in the host defence, we need more mechanistic details in order to interact with neutrophils in a way that would inhibit cancer but not leave the patient at risk of serious infection. Neutrophils can be regulated by – and can regulate the function of – other immune cells, so an important goal is to look at a number of different cell types simultaneously to glean more information about the way that they interact and to uncover potential pathways to modify. By looking across multiple, relevant cancer models we hope to be able to do two things: 1) uncover general mechanisms by which pulmonary neutrophils and their regulation contribute to the cancer microenvironment; and 2) uncover cancers with the strongest or most manipulable interaction with pulmonary neutrophils.


Research activity codes: 2.1 BIOLOGICAL AND ENDOGENOUS FACTORS
Health categories: CANCER AND NEOPLASMS;INFLAMMATORY AND IMMUNE SYSTEM