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

    Gallimore, Awen

    Cancer immunology research

    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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  2. 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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  3. 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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  4. 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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  5. 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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  6. 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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  7. 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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    Ud II Zs.181: Show issues Location:
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  8. Article ; Online: Defining High Endothelial Venules and Tertiary Lymphoid Structures in Cancer.

    Jones, Emma / Gallimore, Awen / Ager, Ann

    Methods in molecular biology (Clifton, N.J.)

    2018  Volume 1845, Page(s) 99–118

    Abstract: High endothelial venules (HEVs) are structurally distinct blood vessels that develop during embryonic and neonatal life in all secondary lymphoid organs except the spleen. HEVs are critical for initiating and maintaining immune responses because they ... ...

    Abstract High endothelial venules (HEVs) are structurally distinct blood vessels that develop during embryonic and neonatal life in all secondary lymphoid organs except the spleen. HEVs are critical for initiating and maintaining immune responses because they extract naïve and memory lymphocytes from the bloodstream, regardless of antigen receptor specificity, and deliver them to antigen-presenting cells inside lymph nodes under homeostatic conditions. HEVs also develop postnatally in nonlymphoid organs during chronic inflammation driven by autoimmunity, infection, allografts, and cancer. Extranodal HEVs are usually surrounded by dense lymphocytic infiltrates organized into lymph-node like, T- and B-cell-rich areas called tertiary lymphoid structures (TLS). HEV neogenesis is thought to facilitate the generation of tissue-destroying lymphocytes inside chronically inflamed tissues and cancers.We are studying the mechanisms underpinning HEV neogenesis in solid cancers and the role of homeostatic T-cell trafficking in controlling cancer immunity. In this chapter we describe methods for identifying HEV in tissue sections of cancerous tissues in humans and mice using immunohistochemical staining for the HEV-specific marker peripheral lymph node addressin (PNAd). L-selectin binding to PNAd is a necessary first step in homeostatic lymphocyte trafficking which is the defining function of HEV. We also describe methods to measure L-selectin-dependent homing of lymphocytes from the bloodstream into lymphoid tissues and tumors in preclinical cancer models.
    MeSH term(s) Animals ; Biomarkers ; Endothelium, Vascular/metabolism ; Humans ; Immunohistochemistry ; L-Selectin/metabolism ; Lymphoid Tissue/immunology ; Lymphoid Tissue/metabolism ; Lymphoid Tissue/pathology ; Mice ; Neoplasms/immunology ; Neoplasms/metabolism ; Neoplasms/pathology ; T-Lymphocyte Subsets/immunology ; T-Lymphocyte Subsets/metabolism ; Tertiary Lymphoid Structures/immunology ; Tertiary Lymphoid Structures/metabolism ; Tertiary Lymphoid Structures/pathology ; Tumor Microenvironment/immunology
    Chemical Substances Biomarkers ; L-Selectin (126880-86-2)
    Language English
    Publishing date 2018-08-24
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't
    ISSN 1940-6029
    ISSN (online) 1940-6029
    DOI 10.1007/978-1-4939-8709-2_7
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  9. 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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  10. Article ; Online: The Dual Role of High Endothelial Venules in Cancer Progression versus Immunity.

    Milutinovic, Stefan / Abe, Jun / Godkin, Andrew / Stein, Jens V / Gallimore, Awen

    Trends in cancer

    2020  Volume 7, Issue 3, Page(s) 214–225

    Abstract: Secondary lymphoid organs (SLOs) are important initiators and regulators of immunity. To carry out this function, the blood vasculature must deliver oxygen and nutrients and recruit circulating lymphocytes into the SLO parenchyma, where they encounter ... ...

    Abstract Secondary lymphoid organs (SLOs) are important initiators and regulators of immunity. To carry out this function, the blood vasculature must deliver oxygen and nutrients and recruit circulating lymphocytes into the SLO parenchyma, where they encounter cognate antigen. High endothelial venules (HEVs) are specialised postcapillary venules that specifically serve this function and are found in all SLOs except spleen. It is becoming clear that alterations to HEV network density and/or morphology can result in immune activation or, as recently implicated, in providing an exit route for tumour cell dissemination and metastases. In this review, the structural plasticity of HEVs, the regulatory pathways underpinning this plasticity, and the relevance of these pathways to cancer progression will be discussed.
    MeSH term(s) Cell Movement/immunology ; Cell Plasticity/immunology ; Disease Progression ; Endothelium, Lymphatic/immunology ; Endothelium, Lymphatic/pathology ; Humans ; Neoplasms/immunology ; Neoplasms/pathology ; Sentinel Lymph Node/immunology ; Sentinel Lymph Node/pathology
    Language English
    Publishing date 2020-10-31
    Publishing country United States
    Document type Journal Article ; Research Support, Non-U.S. Gov't ; Review
    ZDB-ID 2852626-0
    ISSN 2405-8025 ; 2405-8033 ; 2405-8033
    ISSN (online) 2405-8025 ; 2405-8033
    ISSN 2405-8033
    DOI 10.1016/j.trecan.2020.10.001
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