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Article ; Online: Tumor-Associated High Endothelial Venules: Inroads Enabling Immune Control of Cancer Progression.

Gallimore, Awen

2022 Volume 10, Issue 4, Page(s) 371

Abstract: Infiltration of lymphocytes into solid tumors represents a significant bottleneck to successful control of tumor growth. The nature of tumor blood vessels is an important factor governing both quantitative and qualitative features of the immune ... ...

Abstract	Infiltration of lymphocytes into solid tumors represents a significant bottleneck to successful control of tumor growth. The nature of tumor blood vessels is an important factor governing both quantitative and qualitative features of the immune infiltrate. In this issue, Sawada and colleagues identify a genetic signature for blood vessels, most notably high endothelial venules, which are associated with tertiary lymphoid structures and improved clinical outcome. See related article by Sawada et al., p. 468 (4).
MeSH term(s)	Humans ; Lymph Nodes ; Lymphocytes ; Neoplasms/genetics ; Tertiary Lymphoid Structures ; Venules/immunology
Language	English
Publishing date	2022-03-09
Publishing country	United States
Document type	Editorial ; Research Support, Non-U.S. Gov't ; Comment
ZDB-ID	2732489-8
ISSN	2326-6074 ; 2326-6066
ISSN (online)	2326-6074
ISSN	2326-6066
DOI	10.1158/2326-6066.CIR-22-0112
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Article ; Online: The link between T cell activation and development of functionally useful tumour-associated high endothelial venules.

Milutinovic, Stefan / Gallimore, Awen

Discovery immunology

2023 Volume 2, Issue 1, Page(s) kyad006

Abstract: High endothelial venules (HEVs) are specialized postcapillary venules that specifically serve to recruit circulating lymphocytes to secondary lymphoid organs (SLOs) where cognate antigens can be encountered, and immune responses can be initiated. The ... ...

Abstract	High endothelial venules (HEVs) are specialized postcapillary venules that specifically serve to recruit circulating lymphocytes to secondary lymphoid organs (SLOs) where cognate antigens can be encountered, and immune responses can be initiated. The presence of HEV-like vessels in primary human solid tumours and their association with lymphocyte infiltration and favourable clinical outcomes and response to immunotherapy have provided a rationale for therapeutically inducing these vessels in tumours for immunotherapeutic benefit. Here we specifically discuss evidence for a link between T-cell activation and development of useful tumour-associated HEV (TA-HEV). We discuss the molecular and functional features of TA-HEV, highlighting the benefits for promoting tumour immunity and the important unanswered questions that need to be addressed before TA-HEV induction can be optimized for immunotherapeutic benefit.
Language	English
Publishing date	2023-04-24
Publishing country	England
Document type	Journal Article ; Review
ISSN	2754-2483
ISSN (online)	2754-2483
DOI	10.1093/discim/kyad006
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Article ; Online: Immuno-oncology.

Gallimore, Awen / Tournier, Cathy

Essays in biochemistry

2023 Volume 67, Issue 6, Page(s) 903

Abstract: Today, it is accepted that the ability to evade the attention of the immune system is an essential hallmark of cancer. Critically, as tumours progress, cancer cells can protect themselves from the immune system's natural ability to fight the disease. ... ...

Abstract	Today, it is accepted that the ability to evade the attention of the immune system is an essential hallmark of cancer. Critically, as tumours progress, cancer cells can protect themselves from the immune system's natural ability to fight the disease. This observation has led to an explosion of basic research to discover how to restore anti-tumour immunity for advancing cancer treatment. Clinical successes have been achieved following the approval of checkpoint inhibitor therapy to effectively prolong the life of many cancer patients with malignant disease. However, despite impressive survival gains, there is still a high variability of responses between different types of cancer and many patients still fail to respond. The disappointing findings that have been documented over the many clinical trials performed so far coincide with a much more complex view of immuno-oncology that has emerged from technological advances in functional fluorescent imaging techniques, high-throughput RNA sequencing and single-cell mass cytometry. The themed topic 'Immuno-Oncology' captures the contemporary understanding that individual tumours comprise remarkable mixtures of immune cell populations that actively contribute to neoplastic growth, invasion and metastasis through reciprocal and dynamic interactions with cancer cells. In the context of this new knowledge, the reviews discuss novel ideas of therapeutic opportunities for cancer. We would like to thank the authors for their excellent contributions.
MeSH term(s)	Humans ; Neoplasms/therapy ; Syndrome
Language	English
Publishing date	2023-09-25
Publishing country	England
Document type	Editorial ; Research Support, Non-U.S. Gov't
ISSN	1744-1358 ; 0071-1365
ISSN (online)	1744-1358
ISSN	0071-1365
DOI	10.1042/EBC20230071
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Article ; Online: Exploiting ECM remodelling to promote immune-mediated tumour destruction.

Pires, Ana / Burnell, Stephanie / Gallimore, Awen

Current opinion in immunology

2021 Volume 74, Page(s) 32–38

Abstract: Cancer immunotherapy represents a significant breakthrough in cancer treatment mainly due to the ability to harness the activities of cancer-specific T cells. Despite this, most cancers remain resistant to T cell attack. Many reasons have been proposed ... ...

Abstract	Cancer immunotherapy represents a significant breakthrough in cancer treatment mainly due to the ability to harness the activities of cancer-specific T cells. Despite this, most cancers remain resistant to T cell attack. Many reasons have been proposed to explain this, ranging from a lack of antigenicity through to the immunosuppressive effects of the tumour microenvironment. In this review, we examine the relationship between the immune system and a key component of the tumour microenvironment, namely the extracellular matrix (ECM). Specifically, we explore the reciprocal effects of immune cells and the tumour ECM and how the processes underpinning this relationship act to either promote or restrain tumour progression.
MeSH term(s)	Extracellular Matrix ; Humans ; Immunotherapy ; Neoplasms ; T-Lymphocytes/pathology ; Tumor Microenvironment
Language	English
Publishing date	2021-10-07
Publishing country	England
Document type	Journal Article ; Research Support, Non-U.S. Gov't ; Review
ZDB-ID	1035767-1
ISSN	1879-0372 ; 0952-7915
ISSN (online)	1879-0372
ISSN	0952-7915
DOI	10.1016/j.coi.2021.09.006
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Zs.A 2773: Show issues			Location: Je nach Verfügbarkeit (siehe Angabe bei Bestand) bis Jg. 1994: Bestellungen von Artikeln über das Online-Bestellformular Jg. 1995 - 2021: Lesesall (2.OG) ab Jg. 2022: Lesesaal (EG)
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Article ; Online: Sequential targeting of PI3Kδ and LAG3 as an effective anti-cancer approach.

Lauder, Sarah N / Vanhaesebroeck, Bart / Gallimore, Awen

British journal of cancer

2021 Volume 125, Issue 4, Page(s) 467–469

Abstract: Emerging studies have demonstrated the potential of PI3Kδ blockade as an immunotherapy for solid tumours. In pre-clinical models, we recently demonstrated that anti-LAG3 immune checkpoint blockade vastly potentiated PI3Kδ-based immunotherapy, enabling ... ...

Abstract	Emerging studies have demonstrated the potential of PI3Kδ blockade as an immunotherapy for solid tumours. In pre-clinical models, we recently demonstrated that anti-LAG3 immune checkpoint blockade vastly potentiated PI3Kδ-based immunotherapy, enabling successful tumour control in all treated mice.
MeSH term(s)	Animals ; Antigens, CD/immunology ; Class I Phosphatidylinositol 3-Kinases/immunology ; Drug Resistance, Neoplasm/drug effects ; Drug Synergism ; Humans ; Immune Checkpoint Inhibitors/pharmacology ; Immune Checkpoint Inhibitors/therapeutic use ; Immunotherapy ; Mice ; Neoplasms/drug therapy ; Neoplasms/immunology ; Tumor Microenvironment ; Xenograft Model Antitumor Assays ; Lymphocyte Activation Gene 3 Protein
Chemical Substances	Antigens, CD ; Immune Checkpoint Inhibitors ; Class I Phosphatidylinositol 3-Kinases (EC 2.7.1.137) ; PIK3CD protein, human (EC 2.7.1.137) ; Lymphocyte Activation Gene 3 Protein
Language	English
Publishing date	2021-04-06
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/s41416-021-01285-1
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Article: PI3K Isoform Immunotherapy for Solid Tumours.

Scott, Jake / Rees, Lauren / Gallimore, Awen / Lauder, Sarah N

Current topics in microbiology and immunology

2022 Volume 436, Page(s) 369–392

Abstract: Improving the anti-tumour T cell response as a consequence of immunotherapy can result in eradication of tumour burden, however, the majority of patients fail with current treatment regimens and so novel immunotherapies with greater efficacy and improved ...

Abstract	Improving the anti-tumour T cell response as a consequence of immunotherapy can result in eradication of tumour burden, however, the majority of patients fail with current treatment regimens and so novel immunotherapies with greater efficacy and improved tolerability are needed. The phosphoinositide-3-kinase (PI3K) family members that are directly involved in cell signalling comprise PI3Kα, PI3Kβ, PI3Kδ and PI3Kγ, with the latter two isoforms expressed primarily by leukocytes. The survival and optimal function of regulatory T cells (Treg) and myeloid-derived suppressor cells (MDSCs) is dependent on PI3Kδ, whereas tumour-associated macrophages (TAMs), use PI3Kγ. Blocking these signalling isoforms can boost development of effective anti-cancer immune responses and result in control of tumour burden. The dependence on different PI3K isoforms in immune cells makes targeting this pathway an attractive approach for tumour immunotherapy. Herein, we discuss how inhibiting specific PI3K isoforms in pro-tumoural Tregs, MDSCS and TAMs can unleash a powerful anti-tumour immune response, driven by CD8
MeSH term(s)	CD8-Positive T-Lymphocytes ; Humans ; Immune Checkpoint Inhibitors ; Immunotherapy ; Neoplasms/drug therapy ; Phosphatidylinositol 3-Kinase ; Phosphatidylinositol 3-Kinases/genetics ; Phosphatidylinositol 3-Kinases/metabolism ; Phosphatidylinositols/therapeutic use ; Phosphoinositide-3 Kinase Inhibitors ; Protein Isoforms/genetics ; Protein Isoforms/therapeutic use
Chemical Substances	Immune Checkpoint Inhibitors ; Phosphatidylinositols ; Phosphoinositide-3 Kinase Inhibitors ; Protein Isoforms ; Phosphatidylinositol 3-Kinase (EC 2.7.1.137)
Language	English
Publishing date	2022-09-29
Publishing country	Germany
Document type	Journal Article ; Review
ZDB-ID	210099-X
ISSN	0070-217X
ISSN	0070-217X
DOI	10.1007/978-3-031-06566-8_16
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Article ; Online: Structural definition of HLA class II-presented SARS-CoV-2 epitopes reveals a mechanism to escape pre-existing CD4

Chen, Yuan / Mason, Georgina H / Scourfield, D Oliver / Greenshields-Watson, Alexander / Haigh, Tracey A / Sewell, Andrew K / Long, Heather M / Gallimore, Awen M / Rizkallah, Pierre / MacLachlan, Bruce J / Godkin, Andrew

Cell reports

2023 Volume 42, Issue 8, Page(s) 112827

Abstract: ... ...

Abstract	CD4
MeSH term(s)	Humans ; SARS-CoV-2 ; COVID-19 ; HLA-DR1 Antigen ; Epitopes, T-Lymphocyte ; Peptides ; CD4-Positive T-Lymphocytes ; CD8-Positive T-Lymphocytes
Chemical Substances	HLA-DR1 Antigen ; Epitopes, T-Lymphocyte ; Peptides
Language	English
Publishing date	2023-07-19
Publishing country	United States
Document type	Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	2649101-1
ISSN	2211-1247 ; 2211-1247
ISSN (online)	2211-1247
ISSN	2211-1247
DOI	10.1016/j.celrep.2023.112827
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Article ; Online: Regulatory T cells in cancer: where are we now?

Gallimore, Awen / Quezada, Sergio A / Roychoudhuri, Rahul

Immunology

2019 Volume 157, Issue 3, Page(s) 187–189

Abstract: There have been substantial strides forward in our understanding of the contribution of regulatory T (Treg) cells to cancer immunosuppression. In this issue, we present a series of papers highlighting emerging themes on this topic relevant not only to ... ...

Abstract	There have been substantial strides forward in our understanding of the contribution of regulatory T (Treg) cells to cancer immunosuppression. In this issue, we present a series of papers highlighting emerging themes on this topic relevant not only to our understanding of the fundamental biology of tumour immunosuppression but also to the design of new immunotherapeutic approaches. The substantially shared biology of CD4
MeSH term(s)	Animals ; Humans ; Immunotherapy/adverse effects ; Lymphocytes, Tumor-Infiltrating/immunology ; Lymphocytes, Tumor-Infiltrating/pathology ; Neoplasms/immunology ; Neoplasms/pathology ; Neoplasms/therapy ; Phenotype ; Signal Transduction ; T-Lymphocytes, Regulatory/immunology ; T-Lymphocytes, Regulatory/pathology ; Tumor Escape
Language	English
Publishing date	2019-06-21
Publishing country	England
Document type	Editorial ; Introductory Journal Article ; Research Support, Non-U.S. Gov't
ZDB-ID	80124-0
ISSN	1365-2567 ; 0019-2805 ; 0953-4954
ISSN (online)	1365-2567
ISSN	0019-2805 ; 0953-4954
DOI	10.1111/imm.13088
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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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