Dr Leo Carlin - Leukocyte Dynamics
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.
Left: 3D imaging of lung adenocarcinoma. Tumour (green), large blood vessels (red), bronchioles (magenta), perivascular space (yellow). Right: neutrophils in the vasculature of the lung
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.
Kostelec PD, Carlin LM, Glocker B Learning to Detect and Track Cells for Quantitative Analysis of Time-Lapse Microscopic Image Sequences. 2015; IEEE ISBI
Carlin LM, Stamatiades EG, Auffray C, Hanna RN, Glover L, Vizcay-Barrena G, Hedrick CC, Cook HT, Diebold S, Geissmann F Nr4a1-dependent Ly6Clow monocytes monitor endothelial cells and orchestrate their disposal. Cell. 2013; 153: 362-75. (cover image).
Carlin LM, Auffray C, Geissmann F Measuring migration of mouse Ly6Clow monocytes in vivo using intravital microscopy. Current Protocols in Immunology Chapter 14:Unit 14. 2013; 33.1-16
Carlin LM, Evans R, Milewicz H, Fernandes L, Matthews DR, Perani M, Levitt J, Keppler MD, Monypenny J, Coolen A, Barber PR, Vojnovic B, Suhling K, Fraternali F, Ameer-Beg S, Parker PJ, Thomas NS, Ng T A Targeted siRNA Screen Identifies Regulators of Cdc42 Activity at the Natural Killer Cell Immunological Synapse. Science Signaling. 2011 4 . (Co-corresponding author with T.N.)
Education and qualifications
2004: PhD, Imperial College London, Supervisor Dan Davis
2000: BSc (Hons) Immunology, University College London
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
Brownlie D, Doughty-Shenton D, Soong DY, Nixon C, Carragher NO, Carlin LM, Kitamura T. Metastasis-associated macrophages constrain antitumor capability of natural killer cells in the metastatic site at least partially by membrane bound transforming growth factor β. J Immunother Cancer. 2021;9:e001740
Juzenaite G, Secklehner J, Vuononvirta J, Helbawi Y, Mackey JBG, Dean C, Harker JA, Carlin LM, Rankin S, De Filippo K. Lung Marginated and Splenic Murine Resident Neutrophils Constitute Pioneers in Tissue-Defense During Systemic E. coli Challenge. Front Immunol. 2021;12:597595.
Mackey JBG, McFarlane AJ, Jamieson T, Jackstadt R, Raffo-Iraolagoitia XL, Secklehner J, Cortes-Lavaud X, Fercoq F, Clarke W, Hedley A, Gilroy K, Lilla S, Vuononvirta J, Graham GJ, De Filippo K, Murphy DJ, Steele CW, Norman JC, Bird TG, Mann DA, Morton JP, Zanivan S, Sansom OJ, Carlin LM. Maturation, developmental site, and pathology dictate murine neutrophil function. bioRxiv. 2021.
McCowan J, Fercoq F, Kirkwood PM, T'Jonck W, Hegarty LM, Mawer CM, Cunningham R, Mirchandani AS, Hoy A, Humphries DC, Jones GR, Hansen CG, Hirani N, Jenkins SJ, Henri S, Malissen B, Walmsley SR, Dockrell DH, Saunders PTK, Carlin LM, Bain CC. The transcription factor EGR2 is indispensable for tissue-specific imprinting of alveolar macrophages in health and tissue repair. Sci Immunol. 2021 Nov 19;6(65):eabj2132.
Ntala C, Salji M, Salmond J, Officer L, Teodosio AV, Blomme A, McGhee EJ, Powley I, Ahmad I, Kruithof-de Julio M, Thalmann G, Roberts E, Goodyear CS, Jamaspishvili T, Berman DM, Carlin LM, Le Quesne J, Leung HY. Analysis of Prostate Cancer Tumor Microenvironment Identifies Reduced Stromal CD4 Effector T-cell Infiltration in Tumors with Pelvic Nodal Metastasis. Eur Urol Open Sci. 2021;29:19-29.
Fercoq F, Carlin LM. "Mind the GAP": RGS1 hinders antitumor lymphocytes. Nat Immunol. 2021; 22:802-804.
McFarlane AJ, Fercoq F, Coffelt SB, Carlin LM. Neutrophil dynamics in the tumor microenvironment. J Clin Invest. 2021;131: ed2021.
Fercoq F, Remion E, Vallarino-Lhermitte N, Alonso J, Raveendran L, Nixon C, Le Quesne J, Carlin LM, Martin C. Microfilaria-dependent thoracic pathology associated with eosinophilic and fibrotic polyps in filaria-infected rodents. Parasit Vectors. 2020;13(1):551.
Leung EYL, Ennis DP, Kennedy PR, Hansell C, Dowson S, Farquharson M, Spiliopoulou P, Nautiyal J, McNamara S, Carlin LM, Fisher K, Davis DM, Graham G, McNeish IA. NK Cells Augment Oncolytic Adenovirus Cytotoxicity in Ovarian Cancer. Molecular therapy oncolytics. 2020; 16: 289-301.
Muthalagu N, Monteverde T, Raffo-Iraolagoitia X, Wiesheu R, Whyte D, Hedley A, Laing S, Kruspig B, Upstill-Goddard R, Shaw R, Neidler S, Rink C, Karim SA, Gyuraszova K, Nixon C, Clark W, Biankin AV, Carlin LM, Coffelt SB, Sansom OJ, Morton JP, Murphy DJ. Repression of the Type I Interferon pathway underlies MYC & KRAS-dependent evasion of NK & B cells in Pancreatic Ductal Adenocarcinoma. Cancer discovery. 2020;
Pillay J, Tregay N, Juzenaite G, Carlin LM, Pirillo C, Gaboriau DCA, Farahi N, Summers C, Lo Celso C, Chilvers ER, Rankin S, De Filippo K. Effect of the CXCR4 antagonist plerixafor on endogenous neutrophil dynamics in the bone marrow, lung and spleen. Journal of Leukocyte Biology. 2020; 107: 1175– 1185
Plant T, Eamsamarng S, Sanchez-Garcia MA, Reyes L, Renshaw SA, Coelho P, Mirchandani AS, Morgan JM, Ellett FE, Morrison T, Humphries D, Watts ER, Murphy F, Raffo-Iraolagoitia XL, Zhang A, Cash JL, Loynes C, Elks PM, Van Eeden F, Carlin LM, Furley AJW, Whyte MKB, Walmsley SR. Semaphorin 3F signaling actively retains neutrophils at sites of inflammation. The Journal of clinical investigation. 2020;130:3221-3237
Fercoq F, Remion E, Frohberger SJ, Vallarino-Lhermitte N, Hoerauf A, Le Quesne J, Landmann F, Hubner MP, Carlin LM, Martin C. IL-4 receptor dependent expansion of lung CD169+ macrophages in microfilaria-driven inflammation. PLoS neglected tropical diseases. 2019; 13: e0007691.
Mackey JBG, Coffelt SB, Carlin LM. Neutrophil Maturity in Cancer. Frontiers in immunology. 2019; 10: 1912.
McCormick B, Craig HE, Chu JY, Carlin LM, Canel M, Wollweber F, Toivakka M, Michael M, Astier AL, Norton L, Lilja J, Felton JM, Sasaki T, Ivaska J, Hers I, Dransfield I, Rossi AG, Vermeren S. A Negative Feedback Loop Regulates Integrin Inactivation and Promotes Neutrophil Recruitment to Inflammatory Sites. Journal of immunology. 2019;
Patel DF, Peiro T, Bruno N, Vuononvirta J, Akthar S, Puttur F, Pyle CJ, Suveizdyte K, Walker SA, Singanayagam A, Carlin LM, Gregory LG, Lloyd CM, Snelgrove RJ. Neutrophils restrain allergic airway inflammation by limiting ILC2 function and monocyte-dendritic cell antigen presentation. Science immunology. 2019; 4.
Puttur F, Denney L, Gregory LG, Vuononvirta J, Oliver R, Entwistle LJ, Walker SA, Headley MB, McGhee EJ, Pease JE, Krummel MF, Carlin LM, Lloyd CM. Pulmonary environmental cues drive group 2 innate lymphoid cell dynamics in mice and humans. Science immunology. 2019; 4.
Brown E, Carlin LM, Nerlov C, Lo Celso C, Poole, AW. Multiple membrane extrusion sites drive megakaryocyte migration into bone marrow blood vessels. Life Science Alliance. 2018; 1:
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 et al. Inhibition of Endosteal Vascular Niche Remodeling Rescues Hematopoietic Stem Cell Loss in AML. Cell Stem Cell 2018; 22: 64-77 e6
Novo D, Heath N, Mitchell L, Caligiuri G, MacFarlane A, Reijmer D, Charlton L, Knight J, Calka M, McGhee E, Dornier E, Sumpton D, Mason S, Echard A, Klinkert K, et al. Mutant p53s generate pro-invasive niches by influencing exosome podocalyxin levels. Nat Commun 2018; 9: 5069
Riley JS, Quarato G, Cloix C, Lopez J, O'Prey J, Pearson M, Chapman J, Sesaki H, Carlin LM, Passos JF, Wheeler AP, Oberst A, Ryan KM, Tait SW. Mitochondrial inner membrane permeabilisation enables mtDNA release during apoptosis. EMBO J. 2018; 37: e99238.
Tung SL, Boardman DA, Sen M, Letizia M, Peng Q, Cianci N, Dioni L, Carlin LM, Lechler R, Bollati V, Lombardi G, Smyth LA. Regulatory T cell-derived extracellular vesicles modify dendritic cell function. Sci Rep. 2018; 8: 6065.
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
Marco De Donatis