Imperial College London

DrVictoriaMale

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Lecturer in Reproductive Immunology
 
 
 
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v.male

 
 
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Chelsea and Westminster HospitalChelsea and Westminster Campus

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Summary

 

Publications

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47 results found

Male V, Whettlock E, Woon EV, Cuff A, Browne B, Johnson Met al., 2022, Dynamic changes in uterine NK cell subset frequency and function over the menstrual cycle and pregnancy, Frontiers in Immunology, ISSN: 1664-3224

Journal article

Male V, 2022, SARS-CoV-2 infection and COVID-19 vaccination in pregnancy, Nature Reviews Immunology, Vol: 22, Pages: 277-282, ISSN: 1474-1733

SARS-CoV-2 infection poses increased risks of poor outcomes during pregnancy, including preterm birth and stillbirth. There is also developing concern over the effects of SARS-CoV-2 infection on the placenta, and these effects seem to vary between different viral variants. Despite these risks, many pregnant individuals have been reluctant to be vaccinated against the virus owing to safety concerns. We now have extensive data confirming the safety and effectiveness of COVID-19 vaccination during pregnancy, although it will also be necessary to determine the effectiveness of these vaccines specifically against newly emerging viral variants, including Omicron. In this Progress article, I cover recent developments in our understanding of the risks of SARS-CoV-2 infection in pregnancy, and how vaccination can reduce these.

Journal article

Woon EV, Greer O, Shah N, Nikolaou D, Johnson M, Male Vet al., 2022, Number and function of uterine natural killer cells in recurrent miscarriage and implantation failure: a systematic review and meta-analysis, Human Reproduction Update, ISSN: 1355-4786

BACKGROUND: Uterine natural killer cells (uNK) are the most abundant lymphocytes found in the decidua during implantation and in first trimester pregnancy. They are important for early placental development, especially trophoblast invasion and transformation of the spiral arteries. However, inappropriate uNK function has been implicated in reproductive failure, such as recurrent miscarriage (RM) or recurrent implantation failure (RIF). Previous studies have mainly focused on peripheral NK cells (pNK), despite the well-documented differences in pNK and uNK phenotype and function. In recent years, there has been an explosion of studies conducted on uNK, providing a more suitable representation of the immune environment at the maternal-fetal interface. Here, we summarize the evidence from studies published on uNK in women with RM/RIF compared to controls.OBJECTIVE AND RATIONALE: (AUTHOR: edited to journal style.) The objectives of this systematic review and meta-analysis are to evaluate: differences in uNK level in women with RM/RIF compared to controls; pregnancy outcome in women with RM/RIF stratified by high and normal uNK levels; correlation between uNK and pNK in women with RM/RIF; and differences in uNK activity in women with RM/RIF compared to controls.SEARCH METHODS: MEDLINE, EMBASE, Web of Science and Cochrane Trials Registry were searched from inception up to December 2020 and studies were selected in accordance with PRISMA guidelines. Meta-analyses were performed for uNK level, pregnancy outcome and uNK/ pNK correlation. Narrative synthesis was conducted for uNK activity. Risk of bias was assessed by ROBINS-I and publication bias by Egger’s test.OUTCOMES: Our initial search yielded 4636 articles, of which 60 articles were included in our systematic review. Meta-analysis of CD56+ uNK level in women with RM compared to controls showed significantly higher levels in women with RM in subgroup analysis of endometrial samples [standardized mean difference (S

Journal article

Male V, 2022, Menstruation and covid-19 vaccination., BMJ, Vol: 376, Pages: 1-2, ISSN: 1759-2151

Journal article

Male V, 2021, Effect of COVID-19 vaccination on menstrual periods: a retrospective cohort study

<jats:p id="p1">Objective. Clinicians and regulators are receiving reports of changes tomenstrual periods following COVID-19 vaccination. However, it is unclearif the two are biologically linked. If they are, people using hormonalcontraception are predicted to be less likely to report a change andspontaneously cycling people vaccinated prior to ovulation more likely.The objective was to test these hypotheses. Design. Retrospective cohortstudy. Setting. UK. Population. 1273 people who had received at leastone dose of a COVID-19 vaccination, have periods or withdrawal bleedsand keep a record of the dates of these. Methods. Participants reportedwhether they use any hormonal contraception and, for each dose of thevaccine, on which day of their menstrual cycle they were vaccinated anddetails of how the timing and flow of their next period compared totheir normal experience. Main outcome measures. Association between 1.the use of hormonal contraception and reported changes to timing or flowof the next menstrual period, and 2. the timing of vaccination withinthe menstrual cycle and reported changes to timing or flow of the nextmenstrual period. Results. The data from this cohort did not support thepre-specified hypotheses that people using hormonal contraception wouldbe less likely to report a change, or that spontaneously cycling peoplevaccinated prior to ovulation would be more likely to report a change.Conclusions. This study did not detect strong signals supporting theidea that COVID-19 vaccination is linked to menstrual changes in mostpeople. Funding. No specific funding.</jats:p>

Journal article

Male V, 2021, Effect of COVID-19 vaccination on menstrual periods in a retrospectively recruited cohort

<jats:p>Surveillance schemes are receiving increasing numbers of reports from people who have noticed a change to their period following COVID-19 vaccination. In order to investigate this, we retrospectively recruited 1273 people who have a record of their menstrual cycle and vaccination dates and used their reports to explore hypotheses about how COVID-19 vaccination and menstrual changes could be linked. In this dataset, we were unable to detect strong signals to support the idea that COVID-19 vaccination is linked to menstrual changes. However, larger, prospectively recruited studies may be able to find associations that we were not powered to detect.</jats:p>

Journal article

Male V, 2021, Menstrual changes after covid-19 vaccination, BMJ, Vol: 374, Pages: 1-2, ISSN: 1759-2151

Journal article

Dhillon P, Altmann D, Male V, 2021, COVID‐19 vaccines: what do we know so far?, The FEBS Journal, ISSN: 1742-464X

When the novel coronavirus was described in late 2019, it could not have been imagined that within a year, more than 100 vaccine candidates would be in preclinical development and several would be in clinical trials and even approved for use. The scale of the COVID-19 outbreak pushed the scientific community, working in collaboration with pharmaceutical companies, public health bodies, policymakers, funders and governments, to develop vaccines against SARS-CoV-2 at record-breaking speed. As well as driving major amendments to the usual timeframe for bringing a vaccine to fruition, the pandemic has accelerated the development of next-generation technologies for vaccinology, giving rise to two frontrunner RNA vaccines. Although none of the critical safety and efficacy steps have been skipped within the compressed schedules, and the technologies underpinning the novel vaccines have been refined by scientists over many years, a significant proportion of the global population is sceptical of the benefits of COVID-19 vaccines and wary of potential risks. In this interview-based article, we give an overview of how the vaccines were developed and how they work to generate a robust immune response against COVID-19, as well as addressing common questions relating to safety and efficacy.

Journal article

Keestra SM, Male V, Salali GD, 2021, Out of balance: the role of evolutionary mismatches in the sex disparity in autoimmune disease, Medical Hypotheses, Vol: 151, Pages: 1-15, ISSN: 0306-9877

Over the past century autoimmune disease incidence has increased rapidly in (post-) industrialised, affluent societies, suggesting that changes in ecology and lifestyle are driving this development. Epidemiological studies show that (i) 80% of autoimmune disease patients are female, (ii) autoimmune diseases co-occur more often in women, and (iii) the incidence of some autoimmune diseases is increasing faster in women than in men. The female preponderance in autoimmunity is most pronounced between puberty and menopause, suggesting that diverging sex hormone levels during the reproductive years are implicated in autoimmune disease development. Using an evolutionary perspective, we build on the hypotheses that female immunity is cyclical in menstruating species and that natural selection shaped the female immune system to optimise the implantation and gestation of a semi-allogeneic foetus. We propose that cyclical immunomodulation and female immune tolerance mechanisms are currently out of balance because of a mismatch between the conditions under which they evolved and (post-)industrialised, affluent lifestyles. We suggest that current changes in autoimmune disease prevalence may be caused by increases in lifetime exposure to cyclical immunomodulation and ovarian hormone exposure, reduced immune challenges, increased reproductive lifespan, changed reproductive patterns, and enhanced positive energy balance associated with (post-)industrialised, affluent lifestyles. We discuss proximate mechanisms by which oestrogen and progesterone influence tolerance induction and immunomodulation, and review the effect of the menstrual cycle, pregnancy, and contraceptive use on autoimmune disease incidence and symptoms.

Journal article

Male V, 2021, Are COVID-19 vaccines safe in pregnancy? (Mar, 10.1038/s41577-021-00525-y, 2021), Nature Reviews Immunology, Vol: 21, Pages: 268-268, ISSN: 1474-1733

Journal article

Male V, 2021, Are COVID-19 vaccines safe in pregnancy?, Nature Reviews Immunology, Vol: 21, Pages: 200-201, ISSN: 1474-1733

As the COVID-19 vaccination programme starts to be rolled out, many young women are hesitant to accept the vaccine, citing concerns about fertility. Meanwhile, those offered the vaccine during pregnancy must decide whether they will accept, even though pregnant people were excluded from the clinical trials. Data on accidental pregnancies that occurred during the trials and, increasingly, outcomes in pregnant people who receive the vaccine can help these groups to make informed decisions.

Journal article

Woon EV, Day A, Bracewell-Milnes T, Male V, Johnson Met al., 2020, Immunotherapy to improve pregnancy outcome in women with abnormal natural killer cell levels/activity and recurrent miscarriage or implantation failure: A systematic review and meta-analysis., Journal of Reproductive Immunology, Vol: 142, Pages: 1-12, ISSN: 0165-0378

There is a trend towards offering immunotherapy to women with unexplained reproductive failure based on abnormal Natural Killer (NK) cell levels. Previous systematic reviews evaluating immunotherapy usage have not focused on women with abnormal level of NK cells. To address the gap in literature, this systematic review aims to evaluate the efficacy of immunotherapy to improve pregnancy outcome in women with recurrent miscarriage (RM) or implantation failure (RIF) specifically selected based on abnormal levels and/or activity of NK cells. Six databases were searched for peer-reviewed studies following PRISMA guidelines. Risk of bias assessment was conducted using RoB2 for randomized controlled trials (RCT) and ROBINS-I for non-RCT. Of 1025 studies identified, seven studies on intravenous immunoglobulin (IVIG) (four), prednisolone (one), etanercept (one) and intralipid (one) were included. Meta-analysis of the non-RCT IVIG studies (557 participants; 312 intervention, 245 controls) showed livebirth in favour of intervention (RR 2.57; 95 % CI = 1.79-3.69; p < 0.05), however there were significant heterogeneity (I2 = 62 %) and moderate to severe risk of bias in these studies. Individual RCTs reported improved livebirth outcome in etanercept, intralipid and prednisolone and this was significant in the former two (p < 0.05). In conclusion, there may be some benefit of immunotherapy, but paucity of high quality evidence means that it is not possible to support the use of immunotherapy even when selected based on abnormal NK cell level/activity. Further research with application of scientifically validated immunological biomarkers in well-planned large scale RCTs will determine whether immunotherapy is beneficial in this subpopulation of women.

Journal article

Gómez V, Eykyn TR, Mustapha R, Flores-Borja F, Male V, Barber PR, Patsialou A, Green R, Panagaki F, Li CW, Fruhwirth GO, Ros S, Brindle KM, Ng Tet al., 2020, Breast cancer–associated macrophages promote tumorigenesis by suppressing succinate dehydrogenase in tumor cells, Science Signaling, Vol: 13, Pages: 1-13, ISSN: 1945-0877

Tumor-associated macrophages (TAMs) can exist in pro- and anti-inflammatory states. Anti-inflammatory TAMs (also referred to as M2-polarized) generally suppress antitumor immune responses and enhance the metastatic progression of cancer. To explore the mechanisms behind this phenomenon, we isolated macrophages from mice and humans, polarized them ex vivo, and examined their functional interaction with breast cancer cells in culture and in mice. We found that anti-inflammatory TAMs promoted a metabolic state in breast cancer cells that supported various protumorigenic phenotypes. Anti-inflammatory TAMs secreted the cytokine TGF-β that, upon engagement of its receptors in breast cancer cells, suppressed the abundance of the transcription factor STAT1 and, consequently, decreased that of the metabolic enzyme succinate dehydrogenase (SDH) in the tumor cells. The decrease in SDH levels in tumor cells resulted in an accumulation of succinate, which enhanced the stability of the transcription factor HIF1α and reprogrammed cell metabolism to a glycolytic state. TAM depletion-repletion experiments in a 4T1 mouse model additionally revealed that anti-inflammatory macrophages promoted HIF-associated vascularization and expression of the immunosuppressive protein PD-L1 in tumors. The findings suggest that anti-inflammatory TAMs promote tumor-associated angiogenesis and immunosuppression by altering metabolism in breast cancer cells.

Journal article

Cuff AO, Perchet T, Dertschnig S, Golub R, Male Vet al., 2020, Tbet promotes CXCR6 expression in immature NK cells and NK cell egress from the bone marrow, Immunology, Vol: 161, Pages: 28-38, ISSN: 0019-2805

Tbet‐deficient mice have reduced NK cells in blood and spleen, but increased NK cells in bone marrow and lymph nodes, a phenotype that is thought to be due to defective migration. Here, we revisit the role of Tbet in NK cell bone marrow egress. We definitively show that the accumulation of NK cells in the bone marrow of Tbet‐deficient Tbx21 ‐/‐ animals occurs because of a migration defect and identify a module of genes, co‐ordinated by Tbet, which affects the localisation of NK cells in the bone marrow. Cxcr6 is approximately 125‐fold underexpressed in Tbx21 ‐/‐, compared to wild‐type, immature NK cells. Immature NK cells accumulate in the bone marrow of CXCR6‐deficient mice, and CXCR6‐deficient progenitors are less able to reconstitute the peripheral NK cell compartment than their wild‐type counterparts. However, the CXCR6 phenotype is largely confined to immature NK cells, whereas the Tbet phenotype is present in both immature and mature NK cells, suggesting that genes identified as being more differentially expressed in mature NK cells, such as S1pr5 , Cx3cr1 , Sell and Cd69 may therefore be the major drivers of the phenotype.

Journal article

Forrest C, Gomes A, Reeves M, Male Vet al., 2020, NK cell memory to cytomegalovirus: implications for vaccine development, Vaccines, Vol: 8, Pages: 394-394, ISSN: 2076-393X

Natural killer (NK) cells are innate lymphoid cells that recognize and eliminate virally-infected and cancerous cells. Members of the innate immune system are not usually considered to mediate immune memory, but over the past decade evidence has emerged that NK cells can do this in several contexts. Of these, the best understood and most widely accepted is the response to cytomegaloviruses, with strong evidence for memory to murine cytomegalovirus (MCMV) and several lines of evidence suggesting that the same is likely to be true of human cytomegalovirus (HCMV). The importance of NK cells in the context of HCMV infection is underscored by the armory of NK immune evasion genes encoded by HCMV aimed at subverting the NK cell immune response. As such, ongoing studies that have utilized HCMV to investigate NK cell diversity and function have proven instructive. Here, we discuss our current understanding of NK cell memory to viral infection with a focus on the response to cytomegaloviruses. We will then discuss the implications that this will have for the development of a vaccine against HCMV with particular emphasis on how a strategy that can harness the innate immune system and NK cells could be crucial for the development of a vaccine against this high-priority pathogen.

Journal article

Monin L, Whettlock EM, Male V, 2020, Immune responses in the human female reproductive tract, Immunology, Vol: 160, Pages: 106-115, ISSN: 0019-2805

Mucosal surfaces are key interfaces between the host and its environment, but also constitute ports of entry for numerous pathogens. The gut and lung mucosae act as points of nutrient and gas exchange, respectively, but the physiological purpose of the female reproductive tract (FRT) is to allow implantation and development of the fetus. Our understanding of immune responses in the FRT has traditionally lagged behind our grasp of the situation at other mucosal sites, but recently reproductive immunologists have begun to make rapid progress in this challenging area. Here, we review current knowledge of immune responses in the human FRT and their heterogeneity within and between compartments. In the commensal-rich vagina, the immune system must allow the growth of beneficial microbes, whereas the key challenge in the uterus is allowing the growth of the semi-allogeneic fetus. In both compartments, these objectives must be balanced with the need to eliminate pathogens. Our developing understanding of immune responses in the FRT will help us develop interventions to prevent the spread of sexually transmitted diseases and to improve outcomes of pregnancy for mothers and babies.

Journal article

Male V, Cuff AO, Silitto F, Dertschnig S, Hall A, Luong TV, Chakraverty Ret al., 2019, The obese liver environment mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype, Frontiers in Immunology, Vol: 10, Pages: 1-15, ISSN: 1664-3224

The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells in vivo. On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift towards a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.

Journal article

Cuff A, Sillito F, Dertschnig S, Hall A, Luong TV, Chakraverty R, Male Vet al., 2019, TGFβ in the obese liver mediates conversion of NK cells to a less cytotoxic ILC1-like phenotype, Publisher: bioRxiv

The liver contains both NK cells and their less cytotoxic relatives, ILC1. Here, we investigate the role of NK cells and ILC1 in the obesity-associated condition, non-alcoholic fatty liver disease (NAFLD). In the livers of mice suffering from NAFLD, NK cells are less able to degranulate, express lower levels of perforin and are less able to kill cancerous target cells than those from healthy animals. This is associated with a decreased ability to kill cancer cells in vivo. On the other hand, we find that perforin-deficient mice suffer from less severe NAFLD, suggesting that this reduction in NK cell cytotoxicity may be protective in the obese liver, albeit at the cost of increased susceptibility to cancer. The decrease in cytotoxicity is associated with a shift towards a transcriptional profile characteristic of ILC1, increased expression of the ILC1-associated proteins CD200R1 and CD49a, and an altered metabolic profile mimicking that of ILC1. We show that the conversion of NK cells to this less cytotoxic phenotype is at least partially mediated by TGFβ, which is expressed at high levels in the obese liver. Finally, we show that reduced cytotoxicity is also a feature of NK cells in the livers of human NAFLD patients.

Working paper

Evans R, Flores-Borja F, Nassiri S, Miranda E, Lawler K, Grigoriadis A, Monypenny J, Gillet C, Owen J, Gordon P, Male V, Cheung A, Noor F, Barber P, Marlow R, Francesch-Domenech E, Fruhwirth G, Squadrito M, Vojnovic B, Tutt A, Festy F, De Palma M, Ng Tet al., 2019, Integrin-mediated macrophage adhesion promotes lymphovascular dissemination in breast cancer, Cell Reports, Vol: 27, Pages: 1967-1978.e4, ISSN: 2211-1247

Lymphatic vasculature is crucial for metastasis in triple-negative breast cancer (TNBC); however, cellular and molecular drivers controlling lymphovascular metastasis are poorly understood. We define a macrophage-dependent signaling cascade that facilitates metastasis through lymphovascular remodeling. TNBC cells instigate mRNA changes in macrophages, resulting in β4 integrin-dependent adhesion to the lymphovasculature. β4 integrin retains macrophages proximal to lymphatic endothelial cells (LECs), where release of TGF-β1 drives LEC contraction via RhoA activation. Macrophages promote gross architectural changes to lymphovasculature by increasing dilation, hyperpermeability, and disorganization. TGF-β1 drives β4 integrin clustering at the macrophage plasma membrane, further promoting macrophage adhesion and demonstrating the dual functionality of TGF-β1 signaling in this context. β4 integrin-expressing macrophages were identified in human breast tumors, and a combination of vascular-remodeling macrophage gene signature and TGF-β signaling scores correlates with metastasis. We postulate that future clinical strategies for patients with TNBC should target crosstalk between β4 integrin and TGF-β1.

Journal article

Robertson FP, Yeung AC, Male V, Rahman S, Mallett S, Fuller BJ, Davidson BRet al., 2019, Urinary Neutrophil Gelatinase Associated Lipocalins (NGALs) predict acute kidney injury post liver transplant, HPB, Vol: 21, Pages: 473-481, ISSN: 1365-182X

BACKGROUND: Acute Kidney Injury, a common complication of liver transplant, is associated with a significant increase in the risk of morbidity, mortality and graft loss. Current diagnostic criteria leaves a delay in diagnosis allowing further potential irreversible damage. Early biomarkers of renal injury are of clinical importance and Neutrophil Gelatinase Associated Lipocalins (NGALs) and Syndecan-1 were investigated. METHODS: AKI was defined according to the Acute Kidney Injury Network criteria. Urine and blood samples were collected pre-operatively, immediately post-op and 24 h post reperfusion to allow measurement of NGAL and Syndecan-1 levels. RESULTS: 13 of 27 patients developed an AKI. Patients who developed AKI had significantly higher peak transaminases. Urinary NGAL, plasma NGAL and Syndecan-1 levels were significantly elevated in all patients post reperfusion. Urinary NGAL levels immediately post-op were significantly higher in patients who developed an AKI than those that didn't [1319 ng/ml vs 46.56 ng/ml, p ≤ 0.001]. ROC curves were performed and urinary NGAL levels immediately post-op were an excellent biomarker for AKI with an area under the curve of 0.948 (0.847-1.00). CONCLUSIONS: Urinary NGAL levels measured immediately post-op accurately predict the development of AKI and their incorporation into clinical practise could allow early protocols to be developed to treat post transplant AKI.

Journal article

Cuff A, Perchet T, Dertschnig S, Golub R, Male Vet al., 2019, Tbet promotes NK cell bone marrow egress via CXCR6 expression, Publisher: bioRxiv

Tbet-deficient mice have reduced NK cells in blood and spleen, but increased NK cells in bone marrow and lymph nodes, a phenotype that is thought to be due to a defect in S1PR5-mediated migration. Here, we revisit the role of Tbet in NK cell bone marrow egress. We definitively show that the accumulation of NK cells in the bone marrow of Tbet-deficient (Tbx21 −/− ) animals occurs because of a cell-intrinsic migration defect. We identify a profile of gene expression, co-ordinated by Tbet, which affects the localisation of NK cells in the bone marrow. The most underexpressed gene in the absence of Tbet was Cxcr6, and we confirmed that CXCR6 protein was also not expressed in Tbet-deficient NK cells. Cxcr6-expressing ILC progenitors and immature NK cells accumulate in the bone marrow of CXCR6-deficient mice. This suggests that CXCR6 is among the mediators of migration, controlled by Tbet, that work together to coordinate NK cell bone marrow egress. Understanding NK cell bone marrow egress will become increasingly important as we move into an era in which NK cell immunotherapies are being developed.

Working paper

Kostrzewski T, Borg AJ, Meng Y, Filipovic I, Male V, Wack A, DiMaggio PA, Brady HJMet al., 2018, Multiple levels of control determine how E4bp4/Nfil3 regulates NK cell development, Journal of Immunology, Vol: 200, Pages: 1370-1381, ISSN: 0022-1767

The transcription factor E4bp4/Nfil3 has been shown to have a critical role in the development of all innate lymphoid cell types including NK cells. In this study, we show that posttranslational modifications of E4bp4 by either SUMOylation or phosphorylation have profound effects on both E4bp4 function and NK cell development. We examined the activity of E4bp4 mutants lacking posttranslational modifications and found that Notch1 was a novel E4bp4 target gene. We observed that abrogation of Notch signaling impeded NK cell production and the total lack of NK cell development from E4bp4−/− progenitors was completely rescued by short exposure to Notch peptide ligands. This work reveals both novel mechanisms in NK cell development by a transcriptional network including E4bp4 with Notch, and that E4bp4 is a central hub to process extrinsic stimuli.

Journal article

Male V, Stegmann KA, Easom NJ, Maini MKet al., 2017, Natural killer cells in liver disease, Seminars in Liver Disease, Vol: 37, Pages: 198-209, ISSN: 0272-8087

Natural killer (NK) cells comprise one of the most abundant immune cell populations in human liver and the nature and functions of these cells have been a focus of recent interest. Here, we consider the possible roles of NK cells in diverse liver diseases, concentrating on data from patient studies. NK cells can be protective, killing virally infected and cancerous cells in the liver and limiting fibrosis by eliminating hepatic stellate cells. However, they can also be deleterious, contributing to pathology in viral hepatitis by killing hepatocytes and downregulating virus-specific T-cell responses. It has recently emerged that a large fraction of hepatic NK cells constitute a distinct liver-resident subset and we highlight the need to distinguish between circulating and liver-resident NK cells in future studies. There is also a need for further investigation into how NK cells are influenced by the liver microenvironment and what scope there is to harness their immunotherapeutic potential.

Journal article

Cuff AO, Male V, 2017, Conventional NK cells and ILC1 are partially ablated in the livers of Ncr1 iCreTbx21 fl/fl mice [version 2; peer review: 2 approved], Wellcome Open Research, Vol: 2, ISSN: 2398-502X

Mouse liver contains both Eomes-dependent conventional natural killer (cNK) cells and Tbet-dependent liver-resident type I innate lymphoid cells (ILC1). In order to better understand the role of ILC1, we attempted to generate mice that would lack liver ILC1, while retaining cNK, by conditional deletion of Tbet in NKp46+ cells. Here we report that the Ncr1 iCreTbx21 fl/fl mouse has a roughly equivalent reduction in both the cNK and ILC1 compartments of the liver, limiting its utility for investigating the relative contributions of these two cell types in disease models. We also describe the phenotype of these mice with respect to NK cells, ILC1 and NKp46 + ILC3 in the spleen and small intestine lamina propria.

Journal article

Cuff A, Male V, 2017, Conventional NK cells and ILC1 are partially ablated in the livers of Ncr1iCreTbx21fl/fl mice [version 1; peer review: 2 approved with reservations], Wellcome Open Research, Vol: 2, Pages: 1-12, ISSN: 2398-502X

Mouse liver contains both Eomes-dependent conventional natural killer (cNK) cells and Tbet-dependent liver-resident type I innate lymphoid cells (ILC1). In order to better understand the role of ILC1, we attempted to generate mice that would lack liver ILC1, while retaining cNK, by conditional deletion of Tbet in NKp46+ cells. Here we report that the Ncr1iCreTbx21fl/fl mouse has a roughly equivalent reduction in both the cNK and ILC1 compartments of the liver, limiting its utility for investigating the relative contributions of these two cell types in disease models. We also describe the phenotype of these mice with respect to NK cells, ILC1 and NKp46+ ILC3 in the spleen and small intestine lamina propria.

Journal article

Pallett LJ, Davies J, Colbeck EJ, Robertson F, Hansi N, Easom NJW, Burton AR, Stegmann KA, Schurich A, Swadling L, Gill US, Male V, Luong T, Gander A, Davidson BR, Kennedy PTF, Maini MKet al., 2017, IL-2high tissue-resident T cells in the human liver: Sentinels for hepatotropic infection, Journal of Experimental Medicine, Vol: 214, Pages: 1567-1580, ISSN: 0022-1007

The liver provides a tolerogenic immune niche exploited by several highly prevalent pathogens as well as by primary and metastatic tumors. We have sampled healthy and hepatitis B virus (HBV)-infected human livers to probe for a subset of T cells specialized to overcome local constraints and mediate immunity. We characterize a population of T-betloEomesloBlimp-1hiHobitlo T cells found within the intrahepatic but not the circulating memory CD8 T cell pool expressing liver-homing/retention markers (CD69+CD103+ CXCR6+CXCR3+). These tissue-resident memory T cells (TRM) are preferentially expanded in patients with partial immune control of HBV infection and can remain in the liver after the resolution of infection, including compartmentalized responses against epitopes within all major HBV proteins. Sequential IL-15 or antigen exposure followed by TGFβ induces liver-adapted TRM, including their signature high expression of exhaustion markers PD-1 and CD39. We suggest that these inhibitory molecules, together with paradoxically robust, rapid, cell-autonomous IL-2 and IFNγ production, equip liver CD8 TRM to survive while exerting local noncytolytic hepatic immunosurveillance.

Journal article

Male V, Brady HJM, 2017, Murine thymic NK cells: a case of identity, European Journal of Immunology, Vol: 47, Pages: 797-799, ISSN: 0014-2980

Just over a decade ago, it was established that NK cells in the thymus do not follow precisely the same developmental pathway as conventional NK cells that develop in the bone marrow. Subsequently, it has emerged that NK cells are one branch of a family of innate lymphoid cells (ILCs). ILC1s and thymic NK cells have, however, sufficient similarities such that questions have been raised about how distinctive each cell type is from the other. In this issue of European Journal of Immunology, Gabrielli et al. [Eur. J. Immunol. 2017. 47: 800–805] make a detailed study of the transcription factor requirements of murine thymic NK cells. They provide a valuable insight into the distinctive identity of thymic NK cells with regard to Tbet, Nfil3, Id2, and Ets1. In addition, they clarify the nature of DX5 expression on NK cells and ILC‐like cells in the murine thymus.

Journal article

Male V, 2017, Liver-resident NK cells: the human factor, Trends in Immunology, Vol: 38, Pages: 307-309, ISSN: 1471-4981

Mouse liver contains two natural killer (NK) cell populations, one of which recirculates while the other is tissue resident. Following this discovery, several groups have sought to identify liver-resident NK (lrNK) cells in humans. Here, I present an overview of recent advances in the field.

Journal article

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, Gillett CE, Poland SP, Ameer-Beg S, McCaughan F, Carlin LM, Hasan U, Withers DR, Lane P, Vojnovic B, Quezada SA, Ellis P, Tutt ANJ, Ng Tet al., 2017, ROR gamma t(+) innate lymphoid cells promote lymph node metastasis of breast cancers, Cancer Research, Vol: 77, Pages: 1083-1096, ISSN: 0008-5472

Cancer cells tend to metastasize first to tumor-draining lymph nodes, but the mechanisms mediating cancer cell invasion into the lymphatic vasculature remain little understood. Here, we show that in the human breast tumor microenvironment (TME), the presence of increased numbers of RORγt+ group 3 innate lymphoid cells (ILC3) correlates with an increased likelihood of lymph node metastasis. In a preclinical mouse model of breast cancer, CCL21-mediated recruitment of ILC3 to tumors stimulated the production of the CXCL13 by TME stromal cells, which in turn promoted ILC3–stromal interactions and production of the cancer cell motile factor RANKL. Depleting ILC3 or neutralizing CCL21, CXCL13, or RANKL was sufficient to decrease lymph node metastasis. Our findings establish a role for RORγt+ILC3 in promoting lymphatic metastasis by modulating the local chemokine milieu of cancer cells in the TME. Cancer Res; 77(5); 1083–96.

Journal article

Robertson F, Male V, Wright G, Fuller B, Davidson Bet al., 2017, Recruitment of inflammatory monocytes after liver transplantation and correlation with clinical outcome, Spring Meeting on Clinician Scientists in Training, Publisher: Elsevier, Pages: 84-84, ISSN: 0140-6736

Conference paper

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