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Article ; Online: Treg-driven tumour control by PI3Kδ inhibition limits myeloid-derived suppressor cell expansion.

Lauder, Sarah N / Smart, Kathryn / Bart, Valentina M T / Pires, Ana / Scott, Jake / Milutinovic, Stefan / Godkin, Andrew / Vanhaesebroeck, Bart / Gallimore, Awen

British journal of cancer

2022 Volume 127, Issue 9, Page(s) 1595–1602

Abstract: Background: Recent studies have demonstrated that blocking the PI3Kδ signalling enzyme (by administering a small molecule inhibitor, PI-3065) can potently improve the anti-tumour T-cell response through direct inhibition of Tregs. This treatment also ... ...

Abstract	Background: Recent studies have demonstrated that blocking the PI3Kδ signalling enzyme (by administering a small molecule inhibitor, PI-3065) can potently improve the anti-tumour T-cell response through direct inhibition of Tregs. This treatment also has a negative impact on MDSC numbers but the primary mechanism driving this effect has remained unclear. Methods: The 4T1 breast cancer mouse model was used in combination with PI-3065 to gain insights into the effect of PI3Kδ inhibition on MDSCs. Results: PI-3065 treatment resulted in a concomitant reduction in MDSC expansion and tumour size. However, targeting Tregs independent of PI-3065 was also associated with reduced tumour volume and MDSC numbers. Surgical removal of tumours resulted in a rapid and significant decline in MDSC numbers, whilst ex vivo studies using cells from PI-3065-treated mice demonstrated no direct effect of the inhibitor on MDSC activity. Conclusions: Our data suggest that MDSCs are not inhibited directly by PI-3065 treatment but that their reduced recruitment and immunosuppression within the tumour microenvironment is an indirect consequence of PI3Kδ-inhibition-driven tumour control. This indicates that PI3Kδ inhibition drives tumour immunity by breaking down multiple immunosuppressive pathways through both direct mechanisms (on Treg) and indirect mechanisms, secondary to tumour control (on MDSCs).
MeSH term(s)	Animals ; Mice ; Myeloid-Derived Suppressor Cells ; T-Lymphocytes, Regulatory ; Neoplasms ; Tumor Microenvironment ; Cell Proliferation
Language	English
Publishing date	2022-08-19
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-022-01917-0
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Article ; Online: Three-dimensional Imaging Reveals Immune-driven Tumor-associated High Endothelial Venules as a Key Correlate of Tumor Rejection Following Depletion of Regulatory T Cells.

Milutinovic, Stefan / Abe, Jun / Jones, Emma / Kelch, Inken / Smart, Kathryn / Lauder, Sarah N / Somerville, Michelle / Ware, Carl / Godkin, Andrew / Stein, Jens V / Bogle, Gib / Gallimore, Awen

Cancer research communications

2023 Volume 2, Issue 12, Page(s) 1641–1656

Abstract: High endothelial venules (HEV) are specialized post capillary venules that recruit naïve T cells and B cells into secondary lymphoid organs (SLO) such as lymph nodes (LN). Expansion of HEV networks in SLOs occurs following immune activation to support ... ...

Abstract	High endothelial venules (HEV) are specialized post capillary venules that recruit naïve T cells and B cells into secondary lymphoid organs (SLO) such as lymph nodes (LN). Expansion of HEV networks in SLOs occurs following immune activation to support development of an effective immune response. In this study, we used a carcinogen-induced model of fibrosarcoma to examine HEV remodeling after depletion of regulatory T cells (Treg). We used light sheet fluorescence microscopy imaging to visualize entire HEV networks, subsequently applying computational tools to enable topological mapping and extraction of numerical descriptors of the networks. While these analyses revealed profound cancer- and immune-driven alterations to HEV networks within LNs, these changes did not identify successful responses to treatment. The presence of HEV networks within tumors did however clearly distinguish responders from nonresponders. Finally, we show that a successful treatment response is dependent on coupling tumor-associated HEV (TA-HEV) development to T-cell activation implying that T-cell activation acts as the trigger for development of TA-HEVs which subsequently serve to amplify the immune response by facilitating extravasation of T cells into the tumor mass.
MeSH term(s)	Humans ; T-Lymphocytes, Regulatory ; Venules ; Imaging, Three-Dimensional ; Neoplasms ; Lymph Nodes
Language	English
Publishing date	2023-01-27
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ISSN	2767-9764
ISSN (online)	2767-9764
DOI	10.1158/2767-9764.CRC-21-0123
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Article ; Online: Prognostic significance of interleukin-17A-producing colorectal tumour antigen-specific T cells.

Thomson, Amanda / Bento, Diana F Costa / Scurr, Martin J / Smart, Kathryn / Somerville, Michelle S / Keita, Åsa V / Gallimore, Awen / Godkin, Andrew

British journal of cancer

2021 Volume 124, Issue 9, Page(s) 1552–1555

Abstract: Background: The T cell cytokine profile is a key prognostic indicator of post-surgical outcome for colorectal cancer (CRC). Whilst T: Methods: We sought to determine the cytokine profile of circulating tumour antigen-(5T4/CEA) specific T cells of 34 ... ...

Abstract	Background: The T cell cytokine profile is a key prognostic indicator of post-surgical outcome for colorectal cancer (CRC). Whilst T Methods: We sought to determine the cytokine profile of circulating tumour antigen-(5T4/CEA) specific T cells of 34 CRC patients to address whether antigen-specific IL-17A responses were detectable and whether these were distinct to IFN-γ responses. Results: As with IFN-γ-producing T cells, anti-5T4/CEA T Conclusions: Tumour antigen-specific T
MeSH term(s)	Antigens, Neoplasm/immunology ; Case-Control Studies ; Colorectal Neoplasms/immunology ; Colorectal Neoplasms/pathology ; Colorectal Neoplasms/surgery ; Colorectal Surgery/mortality ; Female ; Follow-Up Studies ; Humans ; Interferon-gamma/metabolism ; Interleukin-17/immunology ; Male ; Middle Aged ; Neoplasm Recurrence, Local/immunology ; Neoplasm Recurrence, Local/pathology ; Neoplasm Recurrence, Local/surgery ; Prognosis ; Survival Rate ; Th1 Cells/immunology
Chemical Substances	Antigens, Neoplasm ; IL17A protein, human ; Interleukin-17 ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2021-03-05
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80075-2
ISSN	1532-1827 ; 0007-0920
ISSN (online)	1532-1827
ISSN	0007-0920
DOI	10.1038/s41416-021-01283-3
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Article ; Online: Magnitude of venous or capillary blood-derived SARS-CoV-2-specific T cell response determines COVID-19 immunity.

Scurr, Martin J / Lippiatt, George / Capitani, Lorenzo / Bentley, Kirsten / Lauder, Sarah N / Smart, Kathryn / Somerville, Michelle S / Rees, Tara / Stanton, Richard J / Gallimore, Awen / Hindley, James P / Godkin, Andrew

Nature communications

2022 Volume 13, Issue 1, Page(s) 5422

Abstract: T cells specific for SARS-CoV-2 are thought to protect against infection and development of COVID-19, but direct evidence for this is lacking. Here, we associated whole-blood-based measurement of SARS-CoV-2-specific interferon-γ-positive T cell responses ...

Abstract	T cells specific for SARS-CoV-2 are thought to protect against infection and development of COVID-19, but direct evidence for this is lacking. Here, we associated whole-blood-based measurement of SARS-CoV-2-specific interferon-γ-positive T cell responses with positive COVID-19 diagnostic (PCR and/or lateral flow) test results up to 6 months post-blood sampling. Amongst 148 participants donating venous blood samples, SARS-CoV-2-specific T cell response magnitude is significantly greater in those who remain protected versus those who become infected (P < 0.0001); relatively low magnitude T cell response results in a 43.2% risk of infection, whereas high magnitude reduces this risk to 5.4%. These findings are recapitulated in a further 299 participants testing a scalable capillary blood-based assay that could facilitate the acquisition of population-scale T cell immunity data (14.9% and 4.4%, respectively). Hence, measurement of SARS-CoV-2-specific T cells can prognosticate infection risk and should be assessed when monitoring individual and population immunity status.
MeSH term(s)	Antibodies, Viral ; COVID-19 ; Humans ; Interferon-gamma ; Polymerase Chain Reaction ; SARS-CoV-2 ; T-Lymphocytes
Chemical Substances	Antibodies, Viral ; Interferon-gamma (82115-62-6)
Language	English
Publishing date	2022-09-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2553671-0
ISSN	2041-1723 ; 2041-1723
ISSN (online)	2041-1723
ISSN	2041-1723
DOI	10.1038/s41467-022-32985-8
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Article ; Online: Primary breast tumours but not lung metastases induce protective anti-tumour immune responses after Treg-depletion.

Hughes, Ellyn / Lauder, Sarah N / Smart, Kathryn / Bloom, Anja / Scott, Jake / Jones, Emma / Somerville, Michelle / Browne, Molly / Blainey, Andrew / Godkin, Andrew / Ager, Ann / Gallimore, Awen

Cancer immunology, immunotherapy : CII

2020 Volume 69, Issue 10, Page(s) 2063–2073

Abstract: Although metastatic disease is responsible for the majority of cancer deaths, tests of novel immunotherapies in mouse tumour models often focus on primary tumours without determining whether these therapies also target metastatic disease. This study ... ...

Abstract	Although metastatic disease is responsible for the majority of cancer deaths, tests of novel immunotherapies in mouse tumour models often focus on primary tumours without determining whether these therapies also target metastatic disease. This study examined the impact of depleting Foxp3
MeSH term(s)	Animals ; Female ; Forkhead Transcription Factors/metabolism ; Immunotherapy/methods ; Lung Neoplasms/immunology ; Lung Neoplasms/secondary ; Lung Neoplasms/therapy ; Lymphocyte Depletion/methods ; Lymphocytes, Tumor-Infiltrating/drug effects ; Lymphocytes, Tumor-Infiltrating/immunology ; Mice ; T-Lymphocytes, Regulatory/drug effects ; T-Lymphocytes, Regulatory/immunology ; Triple Negative Breast Neoplasms/immunology ; Triple Negative Breast Neoplasms/pathology ; Triple Negative Breast Neoplasms/therapy
Chemical Substances	Forkhead Transcription Factors ; Foxp3 protein, mouse
Language	English
Publishing date	2020-05-23
Publishing country	Germany
Document type	Journal Article
ZDB-ID	195342-4
ISSN	1432-0851 ; 0340-7004
ISSN (online)	1432-0851
ISSN	0340-7004
DOI	10.1007/s00262-020-02603-x
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Zs.A 1237: Show issues

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Article ; Online: Feeding the child with liver disease: a review and practical clinical guide.

Smart, Kathryn Mary / Alex, George / Hardikar, Winita

Journal of gastroenterology and hepatology

2011 Volume 26, Issue 5, Page(s) 810–815

Abstract: Nourishing children with liver disease is a challenging task; however, appropriate assessment and well-timed nutritional interventions are paramount for a good long-term outcome in these patients. An appropriate balance of macronutrients, micronutrients, ...

Abstract	Nourishing children with liver disease is a challenging task; however, appropriate assessment and well-timed nutritional interventions are paramount for a good long-term outcome in these patients. An appropriate balance of macronutrients, micronutrients, and vitamins is important, as is the route of administration. This review aims to highlight the practical points in nutrition assessment and also provides a guide to the various nutritional interventions available for children with chronic liver disease.
MeSH term(s)	Child ; Child Nutritional Physiological Phenomena ; Child, Preschool ; Chronic Disease ; Humans ; Infant ; Infant, Newborn ; Liver Diseases/complications ; Liver Diseases/diagnosis ; Liver Diseases/physiopathology ; Liver Diseases/therapy ; Malnutrition/diagnosis ; Malnutrition/etiology ; Malnutrition/physiopathology ; Malnutrition/prevention & control ; Nutrition Assessment ; Nutritional Requirements ; Nutritional Status ; Nutritional Support ; Treatment Outcome
Language	English
Publishing date	2011-05
Publishing country	Australia
Document type	Journal Article ; Review
ZDB-ID	632882-9
ISSN	1440-1746 ; 0815-9319
ISSN (online)	1440-1746
ISSN	0815-9319
DOI	10.1111/j.1440-1746.2011.06687.x
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Zs.A 2180: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (1.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Speaking up: teens voice their health information needs.

Smart, Kathryn A / Parker, Randy Spreen / Lampert, Joan / Sulo, Suela

The Journal of school nursing : the official publication of the National Association of School Nurses

2012 Volume 28, Issue 5, Page(s) 379–388

Abstract: School nurses provide an important role in the continuity of health care especially for adolescents who are at high risk for significant health concerns. The purpose of this study was to assess adolescents' health information needs and identify their ... ...

Abstract	School nurses provide an important role in the continuity of health care especially for adolescents who are at high risk for significant health concerns. The purpose of this study was to assess adolescents' health information needs and identify their preferences for accessing health information. Using an inductive qualitative research design, 11 focus groups were conducted with a convenience sample of 101 junior high and high school students in suburban northeastern Illinois. The students identified a variety of health concerns and emphasized the need for accessible, high-quality, and personally relevant information. Most students favored taking an active role in learning about their health. They preferred to directly access information from qualified individuals within comfortable, trusting, and respectful relationships or to indirectly retrieve information from reliable resources. Finally, students emphasized the need for privacy and a variety of learning options depending on the specific health topic.
MeSH term(s)	Adolescent ; Age Factors ; Communication ; Consumer Advocacy ; Female ; Focus Groups ; Health Education/methods ; Health Knowledge, Attitudes, Practice ; Humans ; Illinois ; Information Dissemination ; Learning ; Male ; Needs Assessment ; Qualitative Research ; School Nursing
Language	English
Publishing date	2012-10
Publishing country	United States
Document type	Journal Article ; Research Support, N.I.H., Extramural ; Research Support, Non-U.S. Gov't
ZDB-ID	1217746-5
ISSN	1546-8364 ; 1059-8405 ; 0048-945X
ISSN (online)	1546-8364
ISSN	1059-8405 ; 0048-945X
DOI	10.1177/1059840512450916
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Article ; Online: Characterizing the Randot Preschool stereotest: Testability, norms, reliability, specificity and sensitivity in children aged 2-11 years.

Read, Jenny C A / Rafiq, Sheima / Hugill, Jess / Casanova, Therese / Black, Carla / O'Neill, Adam / Puyat, Vicente / Haggerty, Helen / Smart, Kathryn / Powell, Christine / Taylor, Kate / Clarke, Michael P / Vancleef, Kathleen

PloS one

2019 Volume 14, Issue 11, Page(s) e0224402

Abstract: Purpose: To comprehensively assess the Randot Preschool stereo test in young children, including testability, normative values, test/retest reliability and sensitivity and specificity for detecting binocular vision disorders.: Methods: We tested 1005 ...

Abstract	Purpose: To comprehensively assess the Randot Preschool stereo test in young children, including testability, normative values, test/retest reliability and sensitivity and specificity for detecting binocular vision disorders. Methods: We tested 1005 children aged 2-11 years with the Randot Preschool stereo test, plus a cover/uncover test to detect heterotropia. Monocular visual acuity was assessed in both eyes using Keeler Crowded LogMAR visual acuity test for children aged 4 and over. Results: Testability was very high: 65% in two-year-olds, 92% in three-year-olds and ~100% in older children. Normative values: In 389 children aged 2-5 with apparently normal vision, 6% of children scored nil (stereoblind). In those who obtained a threshold, the mean log threshold was 2.06 log10 arcsec, corresponding to 114 arcsec, and the median threshold was 100 arcsec. Most older children score 40 arcsec, the best available score. We found a small sex difference, with girls scoring slightly but significantly better. Test/retest reliability: ~99% for obtaining any score vs nil. Agreement between stereo thresholds is poor in children aged 2-5; 95% limit of agreement = 0.7 log10 arcsec: five-fold change in stereo threshold may occur without any change in vision. In children over 5, the test essentially acts only as a binary classifier since almost all non-stereoblind children score 40 arcsec. Specificity (true negative rate): >95%. Sensitivity (true positive rate): poor, <50%, i.e. around half of children with a demonstrable binocular vision abnormality score well on the Randot Preschool. Conclusions: The Randot Preschool is extremely accessible for even very young children, and is very reliable at classifying children into those who have any stereo vision vs those who are stereoblind. However, its ability to quantify stereo vision is limited by poor repeatability in children aged 5 and under, and a very limited range of scores relevant to children aged over 5.
MeSH term(s)	Aged ; Child ; Child, Preschool ; Depth Perception/physiology ; Female ; Humans ; Male ; Physical Examination ; Strabismus/diagnosis ; Strabismus/physiopathology ; Vision Disorders/diagnosis ; Vision Disorders/physiopathology ; Vision Tests/methods ; Vision, Binocular/physiology ; Visual Acuity/physiology
Language	English
Publishing date	2019-11-07
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2267670-3
ISSN	1932-6203 ; 1932-6203
ISSN (online)	1932-6203
ISSN	1932-6203
DOI	10.1371/journal.pone.0224402
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Article ; Online: The Ussing chamber system for measuring intestinal permeability in health and disease.

Thomson, Amanda / Smart, Kathryn / Somerville, Michelle S / Lauder, Sarah N / Appanna, Gautham / Horwood, James / Sunder Raj, Lawrence / Srivastava, Brijesh / Durai, Dharmaraj / Scurr, Martin J / Keita, Åsa V / Gallimore, Awen M / Godkin, Andrew

BMC gastroenterology

2019 Volume 19, Issue 1, Page(s) 98

Abstract: Background: The relationship between intestinal epithelial integrity and the development of intestinal disease is of increasing interest. A reduction in mucosal integrity has been associated with ulcerative colitis, Crohn's disease and potentially could ...

Abstract	Background: The relationship between intestinal epithelial integrity and the development of intestinal disease is of increasing interest. A reduction in mucosal integrity has been associated with ulcerative colitis, Crohn's disease and potentially could have links with colorectal cancer development. The Ussing chamber system can be utilised as a valuable tool for measuring gut integrity. Here we describe step-by-step methodology required to measure intestinal permeability of both mouse and human colonic tissue samples ex vivo, using the latest equipment and software. This system can be modified to accommodate other tissues. Methods: An Ussing chamber was constructed and adapted to support both mouse and human tissue to measure intestinal permeability, using paracellular flux and electrical measurements. Two mouse models of intestinal inflammation (dextran sodium sulphate treatment and T regulatory cell depletion using C57BL/6-FoxP3 Results: Distinct regional differences in permeability were consistently identified within mouse and healthy human colon. In particular, mice showed increased permeability in the mid colonic region. In humans the left colon is more permeable than the right. Furthermore, inflammatory conditions induced chemically or due to autoimmunity reduced intestinal integrity, validating the use of the system. Conclusions: The Ussing chamber has been used for many years to measure barrier function. However, a clear and informative methods paper describing the setup of modern equipment and step-by-step procedure to measure mouse and human intestinal permeability isn't available. The Ussing chamber system methodology we describe provides such detail to guide investigation of gut integrity.
MeSH term(s)	Animals ; Colitis/chemically induced ; Colitis/metabolism ; Colon/metabolism ; Dextran Sulfate ; Electrodiagnosis/instrumentation ; Electrodiagnosis/methods ; Fluorescence ; Humans ; Intestinal Mucosa/metabolism ; Mice ; Mice, Inbred C57BL ; Permeability
Chemical Substances	Dextran Sulfate (9042-14-2)
Language	English
Publishing date	2019-06-20
Publishing country	England
Document type	Journal Article
ZDB-ID	2041351-8
ISSN	1471-230X ; 1471-230X
ISSN (online)	1471-230X
ISSN	1471-230X
DOI	10.1186/s12876-019-1002-4
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Article ; Online: Enhanced antitumor immunity through sequential targeting of PI3Kδ and LAG3.

Lauder, Sarah Nicol / Smart, Kathryn / Kersemans, Veerle / Allen, Danny / Scott, Jake / Pires, Ana / Milutinovic, Stefan / Somerville, Michelle / Smart, Sean / Kinchesh, Paul / Lopez-Guadamillas, Elena / Hughes, Ellyn / Jones, Emma / Scurr, Martin / Godkin, Andrew / Friedman, Lori S / Vanhaesebroeck, Bart / Gallimore, Awen

Journal for immunotherapy of cancer

2020 Volume 8, Issue 2

Abstract: Background: Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise ...

Abstract	Background: Despite striking successes, immunotherapies aimed at increasing cancer-specific T cell responses are unsuccessful in most patients with cancer. Inactivating regulatory T cells (Treg) by inhibiting the PI3Kδ signaling enzyme has shown promise in preclinical models of tumor immunity and is currently being tested in early phase clinical trials in solid tumors. Methods: Mice bearing 4T1 mammary tumors were orally administered a PI3Kδ inhibitor (PI-3065) daily and tumor growth, survival and T cell infiltrate were analyzed in the tumor microenvironment. A second treatment schedule comprised PI3Kδ inhibitor with anti-LAG3 antibodies administered sequentially 10 days later. Results: As observed in human immunotherapy trials with other agents, immunomodulation by PI3Kδ-blockade led to 4T1 tumor regressor and non-regressor mice. Tumor infiltrating T cells in regressors were metabolically fitter than those in non-regressors, with significant enrichments of antigen-specific CD8 Conclusions: These data indicate that LAG3 is a key bottleneck to successful PI3Kδ-targeted immunotherapy and provide a rationale for combining PI3Kδ/LAG3 blockade in future clinical studies.
MeSH term(s)	Animals ; Antigens, CD/metabolism ; Class I Phosphatidylinositol 3-Kinases/metabolism ; Female ; Humans ; Immunotherapy/methods ; Mice ; Neoplasms/immunology ; Tumor Microenvironment ; Lymphocyte Activation Gene 3 Protein
Chemical Substances	Antigens, CD ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; Pik3cd protein, mouse (EC 2.7.1.137) ; Lymphocyte Activation Gene 3 Protein
Language	English
Publishing date	2020-10-21
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2719863-7
ISSN	2051-1426 ; 2051-1426
ISSN (online)	2051-1426
ISSN	2051-1426
DOI	10.1136/jitc-2020-000693
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