Lekh N. Dahal

University of Liverpool

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Mark S. Cragg

University of Southampton

Stephen A. Beers

University of Southampton

Frank J. Ward

University of Aberdeen

Kerry L. Cox

University of Southampton

John F. Woolley

Medicines Discovery Catapult

Martin J. Glennie

University of Southampton

Khiyam Hussain

King's College London

Robert N. Barker

University of Aberdeen

Francesco Forconi

University of Southampton

Emma Saulters

University of Liverpool

Cooperative Institutions

University of Southampton

Southampton General Hospital

Cancer Research UK

University Hospital Southampton NHS Foundation Trust

University College London

NIHR CRUK Experimental Cancer Medicine Centre

University of Liverpool

University of Aberdeen

Tenovus Cancer Care

Queen Mary University of London

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FcγRIIB controls antibody-mediated target cell depletion by ITIM-independent mechanisms

Cell Reports (2022)

Alexander P. Simpson Ali Roghanian Robert J. Oldham H. T. Claude Chan Christine A. Penfold

FcgRIIB controls antibody

Fc receptor

10.1016/j.celrep.2022.111099

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Citations (13)

Soluble CTLA-4 raises the threshold for T-cell activation and modulates anti-tumour immunity

bioRxiv (Cold Spring Harbor Laboratory) (2023)

Paul T. Kennedy Emma Saulters Andrew D. Duckworth Yeong Jer Lim John F. Woolley

Abstract CTLA-4 is a crucial immune checkpoint receptor involved in the maintenance of immune homeostasis, tolerance, and tumour control. Antibodies targeting CTLA-4 have been promising treatment for numerous cancers, but the mechanistic basis of their anti-tumoral immune boosting effects are poorly understood. Although the ctla4 gene also encodes an alternatively-spliced soluble variant (sCTLA-4), preclinical/clinical evaluation of anti-CTLA-4-based immunotherapies have not considered the contribution of this isoform. Here, we explore the functional properties of sCTLA-4 and evaluate the efficacy of isoform-specific anti-sCTLA-4 antibody targeting in murine cancer model. We show that expression of sCTLA-4 in tumour cells suppresses CD8 + T-cells in vitro , and accelerates growth and experimental metastasis of murine tumours in vivo . These effects were accompanied by modification of the immune infiltrate, notably restraining CD8 + T-cells in a non-effector state. sCTLA-4 blockade with isoform-specific antibody reversed this restraint, enhancing intratumoural CD8 + T-cell activation and cytolytic potential, correlating with therapeutic efficacy and tumour control. This previously unappreciated role of sCTLA-4 suggests that better understanding of the biology and function of multi-gene products of immune checkpoint receptors needs to be fully elucidated for improved cancer immunotherapy.

Cancer Immunotherapy

CTLA-4

Immune checkpoint

10.1101/2023.06.05.543731

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Citations (2)

Data from STINGing Viral Tumors: What We Know from Head and Neck Cancers

Emma Saulters John F. Woolley Shankar Varadarajan Terence M. Jones Lekh N. Dahal

<div>Abstract<p>It has now become increasingly clear that viruses, which may not be directly oncogenic, can affect the biology of tumors as well as immune behavior against tumors. This has led to a fundamental question: Should tumors associated with viral infection be considered distinct from those without? Typically, viruses activate the host innate immune responses by stimulating pathogen recognition receptors and DNA-sensing pathways, including the stimulator of interferon genes (STING) pathway. However, regulation of the STING pathway in a virus-associated tumor microenvironment is poorly understood. Human papillomavirus (HPV) infection within a subset of head and neck squamous cell carcinomas (HNSCC) promotes a unique etiology and clinical outcome. For reasons currently not well understood, patients with HPV<sup>+</sup> tumors have a better outcome in terms of both overall survival and reduced risk of recurrence compared with HPV<sup>−</sup> HNSCC. This observation may reflect a greater intrinsic immunogenicity associated with HPV infection, pertaining to innate immune system pathways activated following recognition of viral nucleotides. Here we discuss how HNSCC provides a unique model to study the STING pathway in the context of viral-induced tumor type as well as recent advances in our understanding of this pathway in HSNCC.</p></div>

10.1158/0008-5472.c.6513438

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Isolation, Polarization, and Expansion of CD4+ Helper T Cell Lines and Clones Using Magnetic Beads

Methods in molecular biology (2014)

Lekh N. Dahal Robert N. Barker Frank J. Ward

Nucleoprotein

T helper cell

10.1007/978-1-4939-0326-9_18

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Citations (1)

Worked to the bone: antibody-based conditioning as the future of transplant biology

Journal of Hematology & Oncology (2022)

James M. Griffin Fiona Healy Lekh N. Dahal Yngvar Fløisand John F. Woolley

Abstract Conditioning of the bone marrow prior to haematopoietic stem cell transplant is essential in eradicating the primary cause of disease, facilitating donor cell engraftment and avoiding transplant rejection via immunosuppression. Standard conditioning regimens, typically comprising chemotherapy and/or radiotherapy, have proven successful in bone marrow clearance but are also associated with severe toxicities and high incidence of treatment-related mortality. Antibody-based conditioning is a developing field which, thus far, has largely shown an improved toxicity profile in experimental models and improved transplant outcomes, compared to traditional conditioning. Most antibody-based conditioning therapies involve monoclonal/naked antibodies, such as alemtuzumab for graft-versus-host disease prophylaxis and rituximab for Epstein–Barr virus prophylaxis, which are both in Phase II trials for inclusion in conditioning regimens. Nevertheless, alternative immune-based therapies, including antibody–drug conjugates, radio-labelled antibodies and CAR-T cells, are showing promise in a conditioning setting. Here, we analyse the current status of antibody-based drugs in pre-transplant conditioning regimens and assess their potential in the future of transplant biology.

CD52

Immunosuppression

Hematology

10.1186/s13045-022-01284-6

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Citations (21)

Recent Progress in Interferon Therapy for Myeloid Malignancies

Frontiers in Oncology (2021)

Fiona Healy Lekh N. Dahal Jack R.E. Jones Yngvar Fløisand John F. Woolley

Myeloid malignancies are a heterogeneous group of clonal haematopoietic disorders, caused by abnormalities in haematopoietic stem cells (HSCs) and myeloid progenitor cells that originate in the bone marrow niche. Each of these disorders are unique and present their own challenges with regards to treatment. Acute myeloid leukaemia (AML) is considered the most aggressive myeloid malignancy, only potentially curable with intensive cytotoxic chemotherapy with or without allogeneic haematopoietic stem cell transplantation. In comparison, patients diagnosed with chronic myeloid leukaemia (CML) and treated with tyrosine kinase inhibitors (TKIs) have a high rate of long-term survival. However, drug resistance and relapse are major issues in both these diseases. A growing body of evidence suggests that Interferons (IFNs) may be a useful therapy for myeloid malignancies, particularly in circumstances where patients are resistant to existing front-line therapies and have risk of relapse following haematopoietic stem cell transplant. IFNs are a major class of cytokines which are known to play an integral role in the non-specific immune response. IFN therapy has potential as a combination therapy in AML patients to reduce the impact of minimal residual disease on relapse. Alongside this, IFNs can potentially sensitize leukaemic cells to TKIs in resistant CML patients. There is evidence also that IFNs have a therapeutic role in myeloproliferative neoplasms (MPNs) such as polycythaemia vera (PV) and primary myelofibrosis (PMF), where they can restore polyclonality in patients. Novel formulations have improved the clinical effectiveness of IFNs. Low dose pegylated IFN formulations improve pharmacokinetics and improve patient tolerance to therapies, thereby minimizing the risk of haematological toxicities. Herein, we will discuss recent developments and the current understanding of the molecular and clinical implications of Type I IFNs for the treatment of myeloid malignancies.

10.3389/fonc.2021.769628

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Citations (12)

Soluble CTLA-4 attenuates T cell activation and modulates anti-tumor immunity

Molecular Therapy (2023)

Paul T. Kennedy Emma Saulters Andrew D. Duckworth Yeong Jer Lim John F. Woolley

CTLA-4 is a crucial immune checkpoint receptor involved in the maintenance of immune homeostasis, tolerance, and tumor control. Antibodies targeting CTLA-4 have been promising treatments for numerous cancers, but the mechanistic basis of their anti-tumoral immune-boosting effects is poorly understood. Although the ctla4 gene also encodes an alternatively spliced soluble variant (sCTLA-4), preclinical/clinical evaluation of anti-CTLA-4-based immunotherapies have not considered the contribution of this isoform. Here, we explore the functional properties of sCTLA-4 and evaluate the efficacy of isoform-specific anti-sCTLA-4 antibody targeting in a murine cancer model. We show that expression of sCTLA-4 by tumor cells suppresses CD8

CTLA-4

10.1016/j.ymthe.2023.11.028

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Citations (20)

The dichotomy of T helper 17 cells in cancer

Nature reviews. Immunology (2017)

Lekh N. Dahal

10.1038/nri.2017.93

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Citations (12)

Targeting the Alternatively Spliced Soluble Isoform of CTLA-4: Prospects for Immunotherapy?

Immunotherapy (2014)

Frank J. Ward Lekh N. Dahal Rahul C. Khanolkar Sucharita P. Shankar Robert N. Barker

CTLA-4 is an inhibitory protein that contributes to immune homeostasis and tolerance, a role that has led to its exploitation as a therapeutic in several clinical settings including cancer and autoimmune disease. Development of CTLA-4 therapies focused largely on the full-length receptor isoform but other CTLA-4 isoforms are also expressed, including a secretable form of CTLA-4 (soluble CTLA-4 [sCTLA-4]). The contribution of sCTLA-4 to immune regulation has been less well studied, primarily because it was identified some years after the original description of CTLA-4. Here, we examine how sCTLA-4 might contribute to immune regulation and ask whether it might be a biomarker to inform current CTLA-4 therapies or represent a novel CTLA-4 target for future therapeutics.

CTLA-4

Tremelimumab

Cancer Immunotherapy

10.2217/imt.14.73

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Citations (26)

STINGing Viral Tumors: What We Know from Head and Neck Cancers

Cancer Research (2021)

Emma Saulters John F. Woolley Shankar Varadarajan Terence M. Jones Lekh N. Dahal

Abstract It has now become increasingly clear that viruses, which may not be directly oncogenic, can affect the biology of tumors as well as immune behavior against tumors. This has led to a fundamental question: Should tumors associated with viral infection be considered distinct from those without? Typically, viruses activate the host innate immune responses by stimulating pathogen recognition receptors and DNA-sensing pathways, including the stimulator of interferon genes (STING) pathway. However, regulation of the STING pathway in a virus-associated tumor microenvironment is poorly understood. Human papillomavirus (HPV) infection within a subset of head and neck squamous cell carcinomas (HNSCC) promotes a unique etiology and clinical outcome. For reasons currently not well understood, patients with HPV+ tumors have a better outcome in terms of both overall survival and reduced risk of recurrence compared with HPV− HNSCC. This observation may reflect a greater intrinsic immunogenicity associated with HPV infection, pertaining to innate immune system pathways activated following recognition of viral nucleotides. Here we discuss how HNSCC provides a unique model to study the STING pathway in the context of viral-induced tumor type as well as recent advances in our understanding of this pathway in HSNCC.

Sting

10.1158/0008-5472.can-21-0785

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Citations (9)