Leo Carlin - Leukocyte Dynamics

Introduction

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Paradoxically, the immune system can both benefit and antagonise the growth of cancer. Therefore, understanding how the cells of the immune system interact with the cancer microenvironment is of crucial importance. In their updated seminal review 'Hallmarks of Cancer: The Next Generation', Hanahan and Weinberg underline the importance of 'Avoiding immune destruction' and 'Tumour-promoting inflammation' to cancer biology. The immune cell compartment of cancer is composed of tissue resident immune cells 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. In recent years, the field has discovered that immune cells play roles in initiation of primary tumours, tumour maintenance and growth, and in aiding cancer metastasis. Recent success in directing and strengthening the immune system's anti-cancer functions (e.g. Tumour Infiltrating Lymphocyte; TIL therapy and immune check-point inhibition) highlight the potential for new therapies that can come from better understanding of how leukocytes are (dys)regulated in inflammation and cancer. However, current tumour immunotherapy strategies do not work for all patients or cancers.

Immune cells in the inflamed lung (left) and neutrophils in the vasculature of the lung (right):

 carlin image Neutrophils

We aim to better understand the immune system's role at the sites of primary tumour development and at the sites of cancer metastasis. All tumours have some influence on the local vasculature, either modifying it to meet their own needs or using it as a route to spread throughout the body. This has important consequences for our understanding of how the cells of the immune interact with the vasculature. Since it was first studied by microscopy more than 120 years ago, leukocyte extravasation has been refined in molecular detail in the post-capillary vessels, the major sites of immune cell infiltration in many (but, importantly, not all) anatomic sites. The way that leukocytes interact with the specialised vasculature of the lung, spleen, bone marrow, tumour co-opted vasculature and tumour neovasculature are relatively understudied often due to the technical difficulties of imaging some of these vascular beds. Due to the heterogeneity of the vasculature, these are exactly the areas that are least likely to fit the paradigms of leukocyte adhesion and transmigration established in the post-capillary venules. More recently, several innovative techniques have been developed to address these specialised sites by microscopy. This has helped to further investigate mechanisms of immune cell regulation, e.g. showing how immune cells interact with each other at sites of infection or injury to allow fine-tuning of the immune response and a greater portfolio of immune functions to be achieved. Therefore, a thorough examination of the localisation and regulation of leukocytes in situ is a clear unmet need to understand the fundamental mechanisms underlying onco-immunology.

We use advanced light microscopy in combination with other experimental approaches (flow cytometry, proteomics, transcriptomics) to better understand how the regulation of leukocyte dynamics contributes to the tumour environment in the context of both 'avoiding immune-destruction' and 'tumour-promoting inflammation'. Recent data point to multiple levels of immune regulation in cancer development and progression that parallel or redirect pathways that also mediate immune cell homeostasis and inflammation. Our overarching goal is to better understand how cancer evades and exploits the fundamental mechanisms of immune regulation and use this information to uncover new or better therapeutic strategies.

Lab Report

icon Carlin Lab Report

Key Publications

Kostelec PD, Carlin LM, Glocker B, (2015) Learning to Detect and Track Cells for Quantitative Analysis of Time-Lapse Microscopic Image Sequences, IEEE ISBI

L M Carlin, E G Stamatiades, C Auffray, R N Hanna, L Glover, G Vizcay-Barrena, C C Hedrick, H T Cook, S Diebold, F Geissmann (2013). Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. 362-75. Cell 153(2) (cover image).

L M Carlin, C Auffray, F Geissmann (2013) Measuring migration of mouse Ly6Clow monocytes in vivo using intravital microscopy Current Protocols in Immunology Chapter 14:Unit 14.33.1-16

L M Carlin, R Evans, H Milewicz, L Fernandes, D R Matthews, M Perani, J Levitt, M D Keppler, J Monypenny, A Coolen, P R Barber, B Vojnovic, K Suhling, F Fraternali, S Ameer-Beg, P J Parker, N S Thomas, T Ng (2011) A Targeted siRNA Screen Identifies Regulators of Cdc42 Activity at the Natural Killer Cell Immunological Synapse. Science Signaling 4 (201). (Co-corresponding author with T.N.)

Biography

Education and qualifications

2004: PhD, Imperial College London, Supervisor Dan Davis
2000: BSc (Hons) Immunology, University College London

Appointments

2016-present: Group Leader/Head, Beatson Advanced Imaging Resource (BAIR), CRUK Beatson Institute, Glasgow
2013-2016: Lecturer in Respiratory Science/Group Leader, Imperial College London
2009-2013: Postdoctoral Fellow with Frédéric Geissmann, King's College London
2005-2009: Postdoctoral Fellow with Tony Ng, King's College London

Recent Publications

2017

Duarte D, Hawkins ED, Akinduro O, Ang H, De Filippo K, Kong IY, Haltalli M, Ruivo N, Straszkowski L, Vervoort SJ, McLean C, Weber TS, Khorshed R, Pirillo C, Wei A, Ramasamy SK, Kusumbe AP, Duffy K, Adams RH, Purton LE, Carlin LM, Lo Celso C. Inhibition of endosteal vascular niche remodeling rescues hematopoietic stem cell loss in AML. Cell Stem Cell 2018; 22: 64-77.e6. doi: 10.1016/j.stem.2017.11.006. Epub 21 Dec 2017.

Irshad S, Flores-Borja F, Lawler K, Monypenny J, Evans R, Male V, Gordon P, Cheung A, Gazinska P, Noor F, Wong F, Grigoriadis A, Fruhwirth GO, Barber PR, Woodman N, Patel D, Rodriguez-Justo M, Owen J, Martin SG, Pinder SE et al. RORgammat(+) Innate Lymphoid Cells Promote Lymph Node Metastasis of Breast Cancers. Cancer Res 2017; 77: 1083-96

Karadjian G, Fercoq F, Pionnier N, Vallarino-Lhermitte N, Lefoulon E, Nieguitsila A, Specht S, Carlin LM, Martin C. Migratory phase of Litomosoides sigmodontis filarial infective larvae is associated with pathology and transient increase of S100A9 expressing neutrophils in the lung. PLoS Negl Trop Dis 2017; 11: e0005596

Reid SE, Kay EJ, Neilson LJ, Henze AT, Serneels J, McGhee EJ, Dhayade S, Nixon C, Mackey JB, Santi A, Swaminathan K, Athineos D, Papalazarou V, Patella F, Roman-Fernandez A, ElMaghloob Y, Hernandez-Fernaud JR, Adams RH, Ismail S, Bryant DM et al. Tumor matrix stiffness promotes metastatic cancer cell interaction with the endothelium. EMBO J 2017; 36: 2373-89

Secklehner J, Lo Celso C, Carlin LM. Intravital microscopy in historic and contemporary immunology. Immunol Cell Biol 2017; 95: 506-13

2015

Collison JL, Carlin LM, Eichmann M, Geissmann F, Peakman M (2015) Heterogeneity in the Locomotory Behavior of Human Monocyte Subsets over Human Vascular Endothelium In Vitro. J Immunol 195: 1162-70

Kostelec PD, Carlin LM, Glocker B, (2015) Learning to Detect and Track Cells for Quantitative Analysis of Time-Lapse Microscopic Image Sequences, IEEE ISBI

2014

Carlin LM (2014) Imaging intravascular leukocytes. Eur J Clin Invest 44: 13-4

Lab Members

carlin group

Post-docs

Amanda McFarlane
Ximena Raffo

PhD Students

John Mackey (Imperial College London)
Judith Secklehner (Imperial College London)

BAIR

Ewan McGhee
Margaret O'Prey
David Strachan

Research

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Seminars

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