Imperial College London

DrVictoriaMale

Faculty of MedicineDepartment of Metabolism, Digestion and Reproduction

Senior 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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57 results found

Meyerowitz E, Scott J, Richterman A, Male V, Cevik Met al., 2024, Clinical course and management of COVID-19 in the era of widespread population immunity, Nature Reviews Microbiology, Vol: 22, Pages: 75-88, ISSN: 1740-1526

The clinical implications of COVID-19 have changed since SARS-CoV-2 first emerged in humans. The current high levels of population immunity, due to prior infection and/or vaccination, have been associated with a vastly decreased overall risk of severe disease. Some people, particularly those with immunocompromising conditions, remain at risk for severe outcomes. Through the course of the pandemic, variants with somewhat different symptom profiles fromthe original SARS-CoV-2 virus have emerged. The management of COVID-19 has also changed since 2020, with the increasing availability of evidence-based treatments in two main classes: antivirals and immunomodulators. Selecting the appropriate treatment(s) for patients with COVID-19 requires a deep understanding of the evidence and an awareness of the limitations ofapplying data that have been largely based on immune-naïve populations to patients these days who most likely have vaccine- and/or infection-derived immunity. In this review, we provide an overview of the clinical manifestations and approach to caring for adult patientswith COVID-19 in the era of vaccine availability and the dominance of the Omicron subvariants with a focus on the management of COVID-19 in different patient groups, including immunocompromised, pregnant, vaccinated, and unvaccinated patients.

Journal article

Darney BG, Boniface ER, Van Lamsweerde A, Han L, Matteson KA, Cameron S, Male V, Acuna J, Benhar E, Pearson JT, Edelman Aet al., 2023, Impact of coronavirus disease 2019 (COVID-19) vaccination on menstrual bleeding quantity: an observational cohort study, BJOG: an International Journal of Obstetrics and Gynaecology, Vol: 130, Pages: 803-812, ISSN: 1470-0328

OBJECTIVE: To assess whether coronavirus disease 2019 (COVID-19) vaccination impacts menstrual bleeding quantity. DESIGN: Retrospective cohort. SETTING: Five global regions. POPULATION: Vaccinated and unvaccinated individuals with regular menstrual cycles using the digital fertility-awareness application Natural Cycles°. METHODS: We used prospectively collected menstrual cycle data, multivariable longitudinal Poisson generalised estimating equation (GEE) models and multivariable multinomial logistic regression models to calculate the adjusted difference between vaccination groups. All regression models were adjusted for confounding factors. MAIN OUTCOME MEASURES: The mean number of heavy bleeding days (fewer, no change or more) and changes in bleeding quantity (less, no change or more) at three time points (first dose, second dose and post-exposure menses). RESULTS: We included 9555 individuals (7401 vaccinated and 2154 unvaccinated). About two-thirds of individuals reported no change in the number of heavy bleeding days, regardless of vaccination status. After adjusting for confounding factors, there were no significant differences in the number of heavy bleeding days by vaccination status. A larger proportion of vaccinated individuals experienced an increase in total bleeding quantity (34.5% unvaccinated, 38.4% vaccinated; adjusted difference 4.0%, 99.2% CI 0.7%-7.2%). This translates to an estimated 40 additional people per 1000 individuals with normal menstrual cycles who experience a greater total bleeding quantity following the first vaccine dose' suffice. Differences resolved in the cycle post-exposure. CONCLUSIONS: A small increase in the probability of greater total bleeding quantity occurred following the first COVID-19 vaccine dose, which resolved in the cycle after the post-vaccination cycle. The total number of heavy bleeding days did not differ by vaccination status. Our findings can reassure the public that any changes are small and transient

Journal article

Male V, 2023, Vaccine hesitancy: current and future challenges, Immunology and Cell Biology, Vol: 101, Pages: 381-382, ISSN: 0818-9641

Vaccine hesitancy, defined by the WHO as reluctance or refusal to vaccinate, despite the availability of vaccines, threatens to undermine progress in tackling vaccine-preventable disease. In this Immunology Futures article, I explore my experiences of combating vaccine hesitancy, and how research in this area can help. The graphic was made with assets from Freepik.com.

Journal article

Male V, Moffett A, 2023, Natural killer cells in the human uterine mucosa, Annual Review of Immunology, Vol: 41, Pages: 127-151, ISSN: 0732-0582

The presence of granulated lymphocytes in the human uterine mucosa, known as decidua during pregnancy, or endometrium otherwise, was first noted in the nineteenth century, but it was not until 1990 that these cells were identified as a type of natural killer (NK) cell. From the outset, uterine NK (uNK) cells were found to be less cytotoxic than their circulating counterparts, peripheral NK (pNK) cells. Recently, unbiased approaches have defined three subpopulations of uNK cells, all of which cluster separately from pNK cells. Here, we review the history of research into uNK cells, including their ability to interact with placental extravillous trophoblast cells and their potential role in regulating placental implantation. We go on to review more recent advances that focus on uNK cell development and heterogeneity and their potential to defend against infection and to mediate memory effects. Finally, we consider how a better understanding of these cells could be leveraged in the future to improve outcomes of pregnancy for mothers and babies.

Journal article

Forrest C, Chase T, Cuff A, Maroulis D, Motallebzadeh R, Gander A, Davidson B, Griffiths P, Male V, Reeves Met al., 2023, Control of human cytomegalovirus replication by liver resident natural killer cells, Nature Communications, Vol: 14, ISSN: 2041-1723

Natural killer cells are considered to be important for control of human cytomegalovirus– a major pathogen in immune suppressed transplant patients. Viral infection promotes the development of an adaptive phenotype in circulating natural killer cells that changes their anti-viral function. In contrast, less is understood how natural killer cells that reside in tissue respond to viral infection. Here we show natural killer cells resident in the liver have an altered phenotype in cytomegalovirus infected individuals and display increased anti-viral activity against multiple viruses in vitro and identify and characterise a subset of natural killer cells responsible for control. Crucially, livers containing natural killer cells with better capacity to control cytomegalovirus replication in vitro are less likely to experience viraemia post-transplant. Taken together, these data suggest that virally induced expansion of tissue resident natural killer cells in the donor organ can reduce the chance of viraemia post-transplant.

Journal article

Woon EV, Nikolaou D, Maclaran K, Norman-Taylor J, Bhagwat P, Cuff A, Johnson M, Male Vet al., 2023, Uterine NK cells underexpress KIR2DL1/S1 and LILRB1 in reproductive failure, Frontiers in Immunology, Vol: 13, Pages: 1-13, ISSN: 1664-3224

A significant proportion of recurrent miscarriage, recurrent implantation failure and infertility are unexplained, and these conditions have been proposed to have an etiology of immunological dysfunction at the maternal-fetal interface. Uterine Natural Killer cells (uNK) comprise three subsets and are the most numerous immune cells found in the uterine mucosa at the time of implantation. They are thought to play an important role in successful pregnancy by regulation of extravillous trophoblast (EVT) invasion and spiral artery remodelling. Here, we examine the frequency, phenotype and function of uNK1-3 from the uterine mucosa of 16 women with unexplained reproductive failure compared to 11 controls with no reproductive problems, during the window of implantation. We report that KIR2DL1/S1 and LILRB1 expression is lower in the reproductive failure group for both uNK (total uNK, uNK 2 and 3) and pNK. We also show that degranulation activity is significantly reduced in total uNK, and that TNF-α production is lower in all uNK subsets in the reproductive failure group. Taken together, our findings suggest that reproductive failure is associated with global reduction in expression of uNK receptors important for interaction with HLA-C and HLA-G on EVT during early pregnancy, leading to reduced uNK activation. This is the first study to examine uNK subsets during the window of implantation in women with reproductive failure and will serve as a platform to focus on particular aspects of phenotype and function of uNK subsets in future studies. Further understanding of uNK dysregulation is important to establish potential diagnostic and therapeutic targets in the population of women with unexplained reproductive failure.

Journal article

Cocker ATH, Whettlock EM, Browne B, Lai PF, Li JKH, Sivarajasingam SP, Imami N, Johnson MR, Male Vet al., 2022, Isolation of single cells from human uterus in the third trimester of pregnancy: myometrium, decidua, amnion and chorion, Oxford Open Immunology, Vol: 3, Pages: 1-12, ISSN: 2633-6960

During pregnancy, interactions between uterine immune cells and cells of the surrounding reproductive tissues are thought to be vital for regulating labour. The mechanism that specifically initiates spontaneous labour has not been determined, but distinct changes in uterine immune cell populations and their activation status have been observed during labour at term gestation. To understand the regulation of human labour by the immune system, the ability to isolate both immune cells and non-immune cells from the uterus is required. Here, we describe protocols developed in our laboratory to isolate single cells from uterine tissues, which preserve both immune and non-immune cell populations for further analysis. We provide detailed methods for isolating immune and non-immune cells from human myometrium, chorion, amnion and decidua, together with representative flow cytometry analysis of isolated cell populations present. The protocols can be completed in tandem and take approximately 4–5 h, resulting in single-cell suspensions that contain viable leucocytes, and non-immune cells in sufficient numbers for single-cell analysis approaches such as flow cytometry and single cell RNA sequencing (scRNAseq).

Journal article

Male V, 2022, COVID-19 vaccination and menstruation, Science, Vol: 378, Pages: 704-706, ISSN: 0036-8075

Journal article

Edelman A, Boniface ER, Male V, Cameron ST, Benhar E, Han L, Matteson KA, Van Lamsweerde A, Pearson JT, Darney BGet al., 2022, Association between menstrual cycle length and covid-19 vaccination: global, retrospective cohort study of prospectively collected data, BMJ Medicine, Vol: 1, Pages: 1-10, ISSN: 2754-0413

Objectives To identify whether covid-19 vaccines are associated with menstrual changes in order to address concerns about menstrual cycle disruptions after covid-19 vaccination.Design Global, retrospective cohort study of prospectively collected data.Setting International users of the menstrual cycle tracking application, Natural Cycles.Participants 19 622 individuals aged 18-45 years with cycle lengths of 24-38 days and consecutive data for at least three cycles before and one cycle after covid (vaccinated group; n=14 936), and those with at least four consecutive cycles over a similar time period (unvaccinated group; n=4686).Main outcome measures The mean change within individuals was assessed by vaccination group for cycle and menses length (mean of three cycles before vaccination to the cycles after first and second dose of vaccine and the subsequent cycle). Mixed effects models were used to estimate the adjusted difference in change in cycle and menses length between the vaccinated and unvaccinated.Results Most people (n=15 713; 80.08%) were younger than 35 years, from the UK (n=6222; 31.71%), US and Canada (28.59%), or Europe (33.55%). Two thirds (9929 (66.48%) of 14 936) of the vaccinated cohort received the Pfizer-BioNTech (BNT162b2) covid-19 vaccine, 17.46% (n=2608) received Moderna (mRNA-1273), 9.06% (n=1353) received Oxford-AstraZeneca (ChAdOx1 nCoV-19), and 1.89% (n=283) received Johnson & Johnson (Ad26.COV2.S). Individuals who were vaccinated had a less than one day adjusted increase in the length of their first and second vaccine cycles, compared with individuals who were not vaccinated (0.71 day increase (99.3% confidence interval 0.47 to 0.96) for first dose; 0.56 day increase (0.28 to 0.84) for second dose). The adjusted difference was larger in people who received two doses in a cycle (3.70 days increase (2.98 to 4.42)). One cycle after vaccination, cycle length was similar to before the vaccine in individuals

Journal article

Alvergne A, Woon EV, Male V, 2022, Effect of COVID-19 vaccination on the timing and flow of menstrual periods in two cohorts, Frontiers in Reproductive Health, Vol: 4, ISSN: 2673-3153

COVID-19 vaccination protects against the potentially serious consequences of SARS-CoV2 infection, but some people have been hesitant to receive the vaccine because of reports that it could affect menstrual bleeding. To determine whether this occurs we prospectively recruited a cohort of 79 individuals, each of whom recorded details of at least three consecutive menstrual cycles, during which time they each received at least one dose of COVID-19 vaccine. In spontaneously cycling participants, COVID-19 vaccination was associated with a delay to the next period, but this change reversed in subsequent unvaccinated cycles. No delay was detected in those taking hormonal contraception. To explore hypotheses about the mechanism by which these menstrual changes occur, we retrospectively recruited a larger cohort, of 1273 people who had kept a record of their menstrual cycle and vaccination dates. In this cohort, we found a trend towards use of combined hormonal contraception being protective against reporting a delayed period, suggesting that menstrual changes following vaccination may be mediated by perturbations to ovarian hormones. However, we were unable to detect a clear association between the timing of vaccination within the menstrual cycle and reports of menstrual changes. Our findings suggest that COVID-19 vaccination can lengthen the menstrual cycle and that this effect may be mediated by ovarian hormones. Importantly, we find that the menstrual cycle returns to its pre-vaccination length in unvaccinated cycles.

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, Vol: 28, Pages: 548-582, 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, 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, Vol: 13, ISSN: 1664-3224

Uterine Natural Killer cells (uNK) play an important role in promoting successful pregnancy by regulating trophoblast invasion and spiral artery remodelling in the first trimester. Recently, single cell RNA sequencing (scRNAseq) on first trimester decidua showed that uNKs can be divided into three subsets, which may have different roles in pregnancy. Here we present an integration of previously published scRNAseq datasets, together with novel flow cytometry data to interrogate thefrequency, phenotype and function of uNK1-3 in seven stages of the reproductive cycle (menstrual, proliferative, secretory phases of the menstrual cycle; first, second, third trimester; and postpartum). We found that uNK1 and -2 peak in the first trimester, but by the third trimester the majority of uNK are uNK3. All three subsets are most able to degranulate and produce cytokines during the secretory phase of the menstrual cycle and express KIR2D molecules, which allow them to interact with HLA C expressed by placental extravillous trophoblast cells, at the highest frequency during the first trimester. Taken together, our findings suggest that uNK are particularly active and able to interact with placental cells at the time of implantation, and that uNK1 and 2 may be particularly involved in these processes. Our findings are the first to establish how uNK frequency and function changes dynamically across the healthy reproductive cycle. This serves as a platform from which the relationship between uNK function and impaired implantation and placentation can be investigated. This will have important implications for the study of subfertility, recurrent miscarriage, pre31 eclampsia and pre-term labour.

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

Whettlock EM, Woon EV, Cuff AO, Browne B, Johnson MR, Male Vet al., 2022, Dynamic changes in uterine NK cell subset frequency and function over the menstrual cycle and pregnancy

<jats:title>Abstract</jats:title><jats:p>Uterine Natural Killer cells (uNK) play an important role in promoting successful pregnancy by regulating trophoblast invasion and spiral artery remodelling in the first trimester. Recently, single cell RNA sequencing (scRNAseq) on first trimester decidua showed that uNKs can be divided into three subsets, which may have different roles in pregnancy. Here we present an integration of previously published scRNAseq datasets, together with novel flow cytometry data to interrogate the frequency, phenotype and function of uNK1-3 in seven stages of the reproductive cycle (menstrual, proliferative, secretory phases; first, second, third trimester; and postpartum). We found that uNK1 and −2 peak in the first trimester, but by the third trimester the majority of uNK are uNK3. All three subsets are most able to degranulate and produce cytokines during the secretory phase of the menstrual cycle and express KIR2D molecules, which allow them to interact with HLA-C expressed by placental extravillous trophoblast cells, at the highest frequency during the first trimester. Taken together, our findings suggest that uNK are particularly active and able to interact with placental cells at the time of implantation, and that uNK1 and 2 may be particularly involved in these processes. Our findings are the first to establish how uNK frequency and function changes dynamically across the healthy reproductive cycle. This serves as a platform from which the relationship between uNK function and impaired implantation and placentation can be investigated. This will have important implications for the study of subfertility, recurrent miscarriage, pre-eclampsia and pre-term labour.</jats:p>

Working paper

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

Journal article

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

Journal article

Whettlock EM, Von Woon E, Johnson M, Male Vet al., 2021, Phenotype and function of decidual natural killer cells in term labour, Publisher: WILEY, Pages: 150-150, ISSN: 0014-2980

Conference paper

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?, 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

Male V, 2021, Medawar and the immunological paradox of pregnancy: in context., Oxf Open Immunol, Vol: 2

In 1953, Peter Medawar defined 'the immunological paradox of pregnancy', whereby the semi-allogeneic foetus can survive for 9 months in its mother, while a semi-allogeneic graft would be rejected. Here, I revisit the immunological paradox of pregnancy, setting it in the context of the time in which it was proposed. I go on to examine the extent to which Medawar's ideas on the subject have stood the test of time and how they have shaped reproductive immunology.

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

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