Endemic Kaposi's Sarcoma Research Articles

Kaposi sarcoma in an immunocompetent patient: a case report

Kaposi sarcoma (KS) is an uncommon vascular neoplasm associated with human herpes virus 8 (HHV8) infection. Lesions predominantly present at mucocutaneous sites, but may involve other organs. Epidemiological-clinical forms of KS include classic, endemic, AIDS associated and iatrogenic KS. KS is one of the most common AIDS defining malignancy. Lesions evolve from early (patch stage) macule into plaque stage and nodule stage. Diagnosis is made through clinical, histopathological findings and specific immunohistochemical markers for HHV8. Treatment is either by means of destructive procedures and systemic therapy in case of multiorgan involvement. This report is a case of classic KS in a 74-year nondiabetic, non hypertensive female, with no significant surgical, sexual or history of immunosuppression for the occurrence of KS. This case throws light on addressing KS in an immunocompetent patient or a newer variant of KS yet to be researched upon, which can go clinically misdiagnosed due to lack of significant history.

Angioimmunoblastic T-cell lymphoma and Kaposi sarcoma: A fortuitous collision?

Follicular helper T-cell (TFH) lymphoma of the angioimmunoblastic-type (AITL), one of the most prevalent T-cell lymphomas, typically encompasses proliferation of high endothelial venules and Epstein-Barr virus-positive immunoblasts, but neither infection with HHV8 nor association with Kaposi's sarcoma (KS) have been described. The aims of this study are to characterise the association between AITL and HHV8 infection or KS. Three male patients aged 49-76 years, HIV-negative, with concurrent nodal involvement by AITL and KS, were identified from our files and carefully studied. Two patients originated from countries where endemic KS occurs, including one with cutaneous KS. The lymphomas featured abundant vessels, expanded follicular dendritic cells and neoplastic TFH cells [PD1+ (three of three), ICOS+ (three of three), CXCL13+ (three of three), CD10+ (two of three), BCL6 (two of three)] but lacked EBV+ immunoblasts. The foci of KS consisted of subcapsular proliferations of ERG+, CD31+ and/or CD34+ , HHV8+ spindle cells. High-throughput sequencing showed AITL-associated mutations in TET2 (three of three), RHOA (G17V) (three of three) and IDH2 (R172) (two of three), which were absent in the microdissected KS component in two cases. Relapses in two patients consisted of AITL, without evidence of KS. No evidence of HHV8 infection was found in a control group of 23 AITL cases. Concurrent nodal involvement by AITL and KS is rare and identification of both neoplastic components may pose diagnostic challenges. The question of whether the association between AITL and KS may be fortuitous or could reflect the underlying immune dysfunction in AITL remains open.

Comparative polar and lipid plasma metabolomics differentiate KSHV infection and disease states

BackgroundKaposi sarcoma (KS) is a neoplastic disease etiologically associated with infection by the Kaposi sarcoma-associated herpesvirus (KSHV). KS manifests primarily as cutaneous lesions in individuals due to either age (classical KS), HIV infection (epidemic KS), or tissue rejection preventatives in transplantation (iatrogenic KS) but can also occur in individuals, predominantly in sub-Saharan Africa (SSA), lacking any obvious immune suppression (endemic KS). The high endemicity of KSHV and human immunodeficiency virus-1 (HIV) co-infection in Africa results in KS being one of the top 5 cancers there. As with most viral cancers, infection with KSHV alone is insufficient to induce tumorigenesis. Indeed, KSHV infection of primary human endothelial cell cultures, even at high levels, is rarely associated with long-term culture, transformation, or growth deregulation, yet infection in vivo is sustained for life. Investigations of immune mediators that distinguish KSHV infection, KSHV/HIV co-infection, and symptomatic KS disease have yet to reveal consistent correlates of protection against or progression to KS. In addition to viral infection, it is plausible that pathogenesis also requires an immunological and metabolic environment permissive to the abnormal endothelial cell growth evident in KS tumors. In this study, we explored whether plasma metabolomes could differentiate asymptomatic KSHV-infected individuals with or without HIV co-infection and symptomatic KS from each other.MethodsTo investigate how metabolic changes may correlate with co-infections and tumorigenesis, plasma samples derived from KSHV seropositive sub-Saharan African subjects in three groups, (A) asymptomatic (lacking neoplastic disease) with KSHV infection only, (B) asymptomatic co-infected with KSHV and HIV, and (C) symptomatic with clinically diagnosed KS, were subjected to analysis of lipid and polar metabolite profilesResultsPolar and nonpolar plasma metabolic differentials were evident in both comparisons. Integration of the metabolic findings with our previously reported KS transcriptomics data suggests dysregulation of amino acid/urea cycle and purine metabolic pathways, in concert with viral infection in KS disease progression.ConclusionsThis study is, to our knowledge, the first to report human plasma metabolic differentials between in vivo KSHV infection and co-infection with HIV, as well as differentials between co-infection and epidemic KS.

Effectiveness and safety of conventional systemic treatments in classical and endemic Kaposi sarcoma: A multicentric retrospective study of 110 patients.

e21584 Background: Apart from post-transplant Kaposi sarcoma (KS), 2 major subtypes of non-HIV-related KS are described: classical Kaposi sarcoma (CKS) in patients originated from Mediterranean countries and endemic KS (EKS) in patients of sub-Saharan Africa origin. Some patients with aggressive EKS or CKS require systemic treatments among which liposomal anthracycline (LA), taxanes and, to a lesser extent, low dose interferon (LDI) are generally recommended as first lines. Recently, anti-PD1 have shown promising results in an early phase II trial. At the dawn of a turning point in therapeutic era, we aim to map the effectiveness and safety of the main conventional systemic treatments usually available in KS. Methods: We performed a national multicentric retrospective study including all patients receiving a systemic treatment for a histologically proven KS between January 1st 2013 to July 1st 2019. HIV infected patients and patients treated with immunosuppressive drugs were excluded. Overall response was defined as a decrease of more than 50% of lesion area and serious adverse events encompassed grade 3 and 4 toxicity. Results: A total of 110 patients were included. Sixty-nine had CKS (62.7%) and 41 had EKS (37.2) with a median age at diagnosis of 69 (IQR: 57-77) and 41 years (37-59) (p = 0.011), respectively. At the time of diagnosis, EKS was associated with greater systemic involvement compared with CKS (36.6% vs 14.9%, p = 0.017). First-line therapy was initiated within a median of 13.8 months (2.9-43) after KS diagnosis. The 3 main regimens were taxanes (27.3%), LA (19.1%) and LDI (19.1%) with response rates of 82.8%, 80% and 52.6% (p = 0.063), respectively. The cumulative incidence of a second line of treatment in the first 2 years of follow-up was 49.5% (CI95% 38.7-59.4), without significant difference according to the different regimens. Toxicity, regardless of grade, was reported more frequently with LDI (55.3%) and taxanes (47.8%) than with LA (30.4%) (p = 0.035). Poor tolerability led to discontinuation of LDI more frequently than LA (OR = 4.17, p = 0.048), without difference for taxanes. There was no difference in serious adverse events between the 3 main regimens. CKS and EKS didn’t differ regarding overall response rate or time to next treatment regardless of treatment regimens. However, response rates tended to decrease as the lines went on for EKS (from 77.5% in 1st to 33.3% in 3rd line, p = 0.005), in contrast to CKS who maintained a sustained response, with more frequent systemic involvement (56% vs 25.4%, p = 0.002) during EKS course. Conclusions: Herein, we highlight LA, taxanes and LDI are safe and effective treatments for non-immunodeficient KS. Furthermore, EKS differed from CKS, occurring in younger patients, with more frequent systemic involvement and response loss through therapeutic lines, emphasizing the need to evaluate new agents in this form of KS.

Taxonomic reclassification of Kaposi Sarcoma identifies disease entities with distinct immunopathogenesis

BackgroundThe taxonomy of Kaposi Sarcoma (KS) is based on a classification system focused on the description of clinicopathological features of KS in geographically and clinically diverse populations. The classification includes classic, endemic, epidemic/HIV associated and iatrogenic KS, and KS in men who have sex with men (MSM). We assessed the medical relevance of the current classification of KS and sought clinically useful improvements in KS taxonomy.MethodsWe reviewed the demographic and clinicopathological features of 676 patients with KS, who were referred to the national centre for HIV oncology at Chelsea Westminster hospital between 2000 and 2021.ResultsDemographic differences between the different subtypes of KS exist as tautological findings of the current classification system. However, no definitive differences in clinicopathological, virological or immunological parameters at presentation could be demonstrated between the classic, endemic or MSM KS patients. Reclassifying patients as either immunosuppressed or non-immunosuppressed, showed that the immunosuppressed group had a significantly higher proportion of adverse disease features at presentation including visceral disease and extensive oral involvement, classified together as advanced disease (chi2 P = 0.0012*) and disseminated skin involvement (chi2 P < 0.0001*). Immunosuppressed patients had lower CD4 counts, higher CD8 counts and a trend towards higher HHV8 levels compared to non-immunosuppressed patients, however overall survival and disease specific (KS) survival was similar across groups.ConclusionThe current system of KS classification does not reflect meaningful differences in clinicopathological presentation or disease pathogenesis. Reclassification of patients based on the presence or absence of immunosuppression is a more clinically meaningful system that may influence therapeutic approaches to KS.

Distinctive Kaposi Sarcoma-Associated Herpesvirus Serological Profile during Acute Plasmodium falciparum Malaria Episodes.

The seroprevalence of Kaposi sarcoma-associated herpesvirus (KSHV) and the incidence of endemic Kaposi sarcoma (KS) overlap with regions of malaria endemicity in sub-Saharan Africa. Multiple studies have shown an increased risk of KSHV seroconversion in children from high malaria compared to low malaria regions; however, the impact of acute episodes of Plasmodium falciparum (P. falciparum) malaria on KSHV's biphasic life cycle and lytic reactivation has not been determined. Here, we examined KSHV serological profiles and viral loads in 134 children with acute malaria and 221 healthy children from high malaria regions in Kisumu, as well as 77 healthy children from low malaria regions in Nandi. We assayed KSHV, Epstein-Barr virus (EBV), and P. falciparum malaria antibody responses in these three by multiplexed Luminex assay. We confirmed that KSHV seroprevalence was significantly associated with malaria endemicity (OR = 1.95, 1.18-3.24 95% CI, p = 0.01) with 71-77% seropositivity in high-malaria (Kisumu) compared to 28% in low-malaria (Nandi) regions. Furthermore, KSHV serological profiles during acute malaria episodes were distinct from age-matched non-malaria-infected children from the same region. Paired IgG levels also varied after malaria treatment, with significantly higher anti-ORF59 at day 0 but elevated ORF38, ORF73, and K8.1 at day 3. Acute malaria episodes is characterized by perturbation of KSHV latency in seropositive children, providing further evidence that malaria endemicity contributes to the observed increase in endemic KS incidence in sub-Saharan Africa.

Endemic Kaposi's Sarcoma.

Kaposi's sarcoma (KS) is a common neoplasm in Eastern and central Africa reflecting the spread of human gammaherpesvirus-8 (HHV-8), now considered a necessary causal agent for the development of KS. The endemic KS subtype can follow an aggressive clinical course with ulcerative skin lesions with soft tissue invasion or even bone or visceral involvement. In the latter cases, a thorough imaging work-up and better follow-up schedules are warranted. As KS is a chronic disease, the therapeutic goal is to obtain sustainable remission in cutaneous and visceral lesions and a good quality of life. Watchful monitoring may be sufficient in localized cutaneous forms. Potential therapeutic modalities for symptomatic advanced KS include systemic chemotherapies, immunomodulators, immune checkpoint inhibitors, and antiangiogenic drugs.

S1 Guidelines for the Kaposi Sarcoma.

Kaposi's sarcoma (KS) is a rare, malignant, multilocular vascular disease originating from lymphatic endothelial cells that can primarily affect the skin and mucous membranes, but also the lymphatic system and internal organs such as the gastrointestinal tract, lungs or liver. Five epidemiological subtypes of KS with variable clinical course and prognosis are distinguished, with increased incidence in specific populations: (1) Classical KS, (2) Iatrogenic KS in immunosuppression, (3) Endemic (African) lymphadenopathic KS, (4) Epidemic, HIV-associated KS and KS associated with immune reconstitution inflammatory syndrome (IRIS), and (5) KS in men who have sex with men (MSM) without HIV infection. This interdisciplinary guideline summarizes current practice-relevant recommendations on diangostics and therapy of the different forms of KS. The recommendations mentioned in this short guideline are elaborated in more detail in the extended version of the guideline (online format of the JDDG).

Cutaneous and subcutaneous Kaposi's sarcoma lesions treated with electrochemotherapy.

Kaposi's sarcoma (KS) is a locally aggressive mesenchymal tumor that involves the lymphovascular system, with a tendency to become multifocal. Electrochemotherapy (ECT) is considered a valuable treatment option in selected patients with cutaneous and subcutaneous KS lesions. We report a retrospective study that included 14 classic and endemic KS patients that underwent ECT sessions for the treatment of KS cutaneous and subcutaneous lesions at our institution. According to Response Evaluation Criteria in Solid Tumors (RECIST) version 1.1 criteria, our patients had an overall response rate (ORR) of 100% to the ECT treatment. A complete response (CR) was obtained in 92.8% of patients after one or more ECT sessions. Only one patient had a progressive disease (PD). The treatment was well tolerated with a low complication rate, mainly transitory local pain or skin ulceration. ECT represents a locoregional therapy for containment and symptomatic control of classic and endemic KS cutaneous and subcutaneous lesions. Further studies including different subtypes of KS patients should also be performed.

Kaposi Sarcoma with Mucocutaneous Involvement in French Guiana: An Epidemiological Study between 1969 and 2019.

Data on Kaposi sarcoma in French Guiana are scarce and out of date. This territory presents unique epidemiological features. The objectives of this retrospective study were to analyse the clinical features, outcome and incidence of the different forms of Kaposi sarcoma in patients diagnosed between 1969 and 2019. The study population comprised a total of 52 patients. Clinical forms included epidemic Kaposi sarcoma (n=30), endemic (n=18), iatrogenic (n=2), classic (n=1) and unclassified Kaposi sarcoma (n=1). The mean annual incidence rate of epidemic Kaposi reached a peak in the 1990s (0.93/100,000) then decreased in the 2000s (0.33/100,000), while the incidence of endemic Kaposi sarcoma reached a peak in the 1980s (0.82/100,000) before decreasing in the 2000s (0.12/100,000). Factors associated with the epidemic form were: sexual intercourse between men (p=0.0054) and Haitian origin (p=0.035). The presence of nodules and/or tumour, lesions limited to the lower limbs, and age >65 years were associated with the endemic form. While Creole populations seem to be as affected by endemic Kaposi sarcoma as their African counterparts, the dynamics of Kaposi sarcoma in French Guiana are now dominated by the epidemic form.

Pembrolizumab Is Safe and Effective in Kaposi Sarcoma.

Antitumor activity was observed with pembrolizumab in classic and endemic Kaposi sarcoma.

A Case of Neglected Classıc Kaposı’s Sarcoma

Kaposi's sarcoma (KS) is a rare disease in the community. It was first described in 1872 as an idiopathic, multipigmented sarcoma of the skin [1]. It is a vascular or lymphatic-focused tumor type originating from the endothelium, caused by Human Herpes Virus 8 (HHV8), called KS-associated herpes virus (KSHV) [2]. There are 4 clinical subtypes of the disease. These are: Classical KS, African endemic KS, iatrogenic KS, and AIDS-related (epidemic) KS. It usually occurs with pink-red patch and blue-purple-black nodule, polyp or plaques. Most of the cases in classical KS are over 50 years old. Although the female/male ratio varies between studies, it is more common in males [3]. Here, a neglected case of Classic KS is presented.

Inhibitory KIR2DL2 receptor and HHV-8 in classic or endemic Kaposi sarcoma

KIR2DL2, an inhibitory Killer cell Immunoglobulin-like Receptor (KIR), has been shown to predispose to the development of several herpesvirus-associated diseases by inhibiting the efficiency of Natural Killer (NK) cells against virus-infected cells. The aim of this observational study was to assess the prevalence of KIR2DL2 and Human Herpes Virus 8 (HHV8) in patients affected with classical and endemic Kaposi sarcoma (KS), as well as in controls. Blood samples collected from 17 Caucasian, HIV-negative, immunocompetent patients affected with classical KS (c-KS), 12 African, HIV-negative patients with endemic KS (e-KS), 83 healthy subjects and 26 psoriatic patients were processed for genotypization by PCR for two KIR alleles, such as KIR2DL2 and KIR2DL3 and analyzed for HHV-8 presence. The totality of both c-KS and e-KS patients presented HHV-8 infection, whereas HHV8 was found in 26.9% of psoriatic subjects and 19.3% of healthy subjects. KIR2DL2 was found in the 76.5% of c-KS subjects, while the receptor was found in 41.7% of the e-KS group, 34.6% of psoriatic patients and 43.4% of healthy controls (p < 0.0001). A significantly higher prevalence of KIR2DL2 in c-KS patients than in all the other subjects was also confirmed comparing age-matched groups. Based on these results, the inhibitory KIR2DL2 genotype appears to be a possible cofactor which increases the risk of developing c-KS in HHV8-positive, immunocompetent subjects, while it seems less relevant in e-KS pathogenesis.

Current and Future Tools for Diagnosis of Kaposi's Sarcoma.

Simple SummaryKaposi’s sarcoma, a rare opportunistic tumor, is observed in four epidemiological conditions (AIDS-related, iatrogenic, endemic or classic KS). Although in most cases KS is an indolent disease, it can be locally aggressive and/or it can invade other organs than the skin, resulting in more severe presentations, especially in patients with severe immunosuppression. There is no consensus on the imaging workup that is necessary for either the initial staging of the disease or the follow-up. Future perspectives include the use of certain non-invasive imaging tools that may help to evaluate the clinical response to treatment, as well as certain new histological markers that may help in guiding the treatment planning for this atypical neoplasm.Kaposi’s sarcoma (KS) is a rare, atypical malignancy associated with immunosuppression and can be qualified as an opportunistic tumor, which responds to immune modulation or restoration. Four different epidemiological forms have been individualized (AIDS-related, iatrogenic, endemic or classic KS). Although clinical examination is sufficient to diagnose cutaneous lesions of KS, additional explorations are necessary in order to detect lesions involving other organs. New histological markers have been developed in recent years concerning the detection of HHV-8 latent or lytic proteins in the lesions, helping to confirm the diagnosis when it is clinically doubtful. More recently, the evaluation of the local immune response has also been shown to provide some guidance in choosing the appropriate therapeutic option when necessary. We also review the indication and the results of conventional radiological imaging and of non-invasive imaging tools such as 18F-fluoro-deoxy-glucose positron emission tomography, thermography and laser Doppler imaging for the diagnosis of KS and for the follow-up of therapeutic response in patients requiring systemic treatment.

Long-term outcomes for children and adolescents with Kaposi sarcoma.

Kaposi sarcoma (KS) is one of the most common childhood cancers in eastern and central Africa. It has become a treatable disease with increasing availability of antiretroviral therapy (ART) and chemotherapy. We aimed to fill the data gap in establishing whether long-term survival is achievable for children in low-income countries. We retrospectively analysed data for children and adolescents aged ≤18.9years diagnosed with HIV-related or endemic KS from 2006 to 2015 who received standardized institutional treatment regimens utilizing chemotherapy plus ART (if HIV-positive) at a tertiary care public hospital in Lilongwe, Malawi. Long-term survival was analysed and mortality was associated with KS for those with refractory/progressive disease at the time of death. There were 207 children/adolescents with KS (90.8% HIV-related); 36.7% were alive, 54.6% had died, and 8.7% had been lost to follow-up. The median follow-up time for survivors was 6.9years (range 4.2-13.9 years). Death occurred at a median of 5.3months after KS diagnosis (range 0.1-123 months). KS progression was associated with mortality for most (61%) early deaths (survival time of < 6months); conversely, KS was associated with a minority (31%) of late-onset deaths (after 24months). The 7-year overall survival was 37% [95% confidence interval (CI) 30-44%] and was higher for those diagnosed between 2011 and 2015 compared to 2006-2010: 42% (95% CI 33-51%) versus 29% (95% CI 20-39%), respectively (P=0.01). Among the 66 HIV-positive survivors, 58% were still on first-line ART. Long-term survival is possible for pediatric KS in low-resource settings. Despite better survival in more recent years, there remains room for improvement.

Systemic Treatment Initiation in Classical and Endemic Kaposi's Sarcoma: Risk Factors and Global Multi-State Modelling in a Monocentric Cohort Study.

Simple SummaryOver the past decades, clinical features and patients’ outcome of iatrogenic and HIV-related KS epidemiological subtypes have been widely described in large cohort series. Due to their lower incidence and the limited resources available in endemic KS countries, classical and endemic KS epidemiological studies remain scarce, thus increasing the challenge of such clinically heterogeneous chronic diseases’ management. In this large retrospective cohort study, six risk factors for treatment initiation were identified: time between first symptoms and diagnosis ≥1 year, endemic KS, total number of lesions ≥10, visceral or head/neck localization and edema. No response or treatment-free time difference was observed between the most frequently used therapeutic options: chemotherapy and interferon-alpha. Assessment for systemic treatment risk factors provides guidance for adequate follow-up and patients’ information on disease outcome. Absence of efficacy difference between systemic regimens allows treatment choice based on fitness.Background: Although several studies described the clinical course of epidemic and post-transplant Kaposi’s Sarcoma (KS), the lack of large cohorts of classic/endemic KS, precluded such characterization. Methods: We used multi-state modelling in a retrospective monocentric study to evaluate global disease evolution and identify risk factors for systemic treatment (ST) initiation. 160 classic/endemic KS patients consecutively diagnosed between 1990 and 2013 were included. Results: 41.2% of classic/endemic KS patients required ST. Cumulative incidence of ST after 2 years of follow-up was 28.4% [95% CI: 20.5; 35.5]. Multivariate analysis identified six risk factors for ST initiation: time between first symptoms and diagnosis ≥1 year, endemic KS, total number of lesions ≥10, visceral, head or neck localization and presence of edema. Type of ST, type of KS, age and time between diagnosis and ST were not associated with response. Mean treatment-free time during the first 5 years following ST was 44 months for interferon and 44.6 months for chemotherapy treated patients (Mean difference: −0.5 months [95% CI: −9.5; 4.9]). Conclusions: Our study reveals ST risk factors in classic/endemic KS and highlights the clinical aggressiveness of the endemic KS subtype. No efficacy difference was observed between standard of care treatments, enabling treatment choice based on patient’s fitness.

1077MO PD1 blockade with pembrolizumab in classic and endemic Kaposi sarcoma: A multicenter phase II study

While the treatment of iatrogenic and HIV-related KS is well defined, mostly based on restoring the immune function, the treatment of classic/endemic KS is less codified. Chemotherapy or interferon are used for patients (pts) with extensive cutaneous and/or visceral KS but the tolerance may be poor in elderly pts, and long-term remissions are rare. Major efficacy of PD1 blockade has been demonstrated in Merkel cell carcinoma, another virus-induced tumor, in part driven by the immunogenicity of virus-associated antigens.

Epidemiology of Kaposi's sarcoma in Zambia, 2007 - 2014.

Kaposi's sarcoma (KS) is the most prevalent HIV and AIDS-associated cancer in the world. Zambia has been considered as part of the "KS belt", where endemic KS has been prevalent. This study, therefore, aimed to present the descriptive epidemiology of Kaposi's sarcoma in Zambia from 2007 - 2014. We conducted the descriptive epidemiology of Kaposi's sarcoma in Zambia nested on two data sources; the Zambia National Cancer Registry (ZNCR) Kaposi's sarcoma (KS) data, and population-based HIV data from the Zambia National AIDS Council (NAC). Central Statistics Office (CSO) demographic data were used to determine the prevalence and annual incidence of KS. KS sample was 2521while HIV data from NAC were already population-based (HIV impact assessment survey). We used Microsoft Excel and SPSS version 21 in graphical computation and statistical analyses. Both HIV and KS were highly prevalent in Lusaka, Central, and Southern provinces. ART coverage ranged from 40% - 60%; HIV prevalence was 14.9% in females and 9.5% in males while KS prevalence was 13/100,000 in females and 21/100,000 in males. HIV prevalence was associated with KS prevalence with r = 0.827 and a p-value of 0.001 in males, and r = 0.898 with a p-value of 0.000 in females. There were 61% confirmed HIV seropositive KS, 18% confirmed HIV seronegative KS and 21% unknown HIV status KS. The high prevalence of KS in Zambia is as a result of the high prevalence of HIV. The identified two key interventions for the reduction of KS morbidity are; reducing HIV infection rate and improving ART coverage across the country.

Lack of CD8+ T-cell co-localization with Kaposi's sarcoma-associated herpesvirus infected cells in Kaposi's sarcoma tumors.

Despite the close association between Kaposi’s sarcoma (KS) and immune dysfunction, it remains unclear whether tumor infiltrating immune cells (TIIC), by their absence, presence, or dysfunction, are mechanistically correlated with KS pathogenesis. Therefore, their potential capacity to serve as prognostic biomarkers of KS disease progression or control is unclear. Because epidemic-KS (EpKS) occurs with HIV-1 co-infection, it is particularly important to compare TIIC between EpKS and HIV-negative African endemic-KS (EnKS) to dissect the roles of HIV-1 and Kaposi Sarcoma-associated herpesvirus (KSHV) in KS pathogenesis. This cross-sectional study of 13 advanced KS (4 EnKS, 9 EpKS) patients and 3 healthy controls utilized single-color immunohistochemistry and dual-color immunofluorescence assays to characterize and quantify KSHV infected cells in relation to various TIIC in KS biopsies. Analysis of variance (ANOVA) and Mann-Whitney tests were used to assess differences between groups where P-values < 0.05 were considered significant. The abundance of KSHV infected cells was heterogeneous in KS biopsies. Despite the presence of T-cell chemoattractant chemokine CxCL-9 in biopsies, CD8+ T-cells were sparsely distributed in regions with evident KSHV infected cells but were readily detectable in regions devoid of KSHV infected cells (P < 0.0001). CD68+ (M1) macrophages were evenly and diffusely distributed in KS biopsies, whereas, the majority of CD163+ (M2) macrophages were localized in regions devoid of KSHV infected cells (P < 0.0001). Overall, the poor immune cell infiltration or co-localization in KS biopsies independent of HIV-1 co-infection suggests a fundamental tumor immune evasion mechanism that warrants further investigation.

The Kaposi's Sarcoma-Associated Herpesvirus (KSHV) gH/gL Complex Is the Predominant Neutralizing Antigenic Determinant in KSHV-Infected Individuals.

Kaposi’s sarcoma-associated herpesvirus (KSHV) is the etiological agent of Kaposi’s sarcoma (KS), one of the most prevalent cancers of people living with HIV/AIDS in sub-Saharan Africa. The seroprevalence for KSHV is high in the region, and no prophylactic vaccine against the virus is available. In this study, we characterized the antigenic targets of KSHV-specific neutralizing antibodies (nAbs) in asymptomatic KSHV-infected individuals and KS patients with high nAbs titers. We quantified the extent to which various KSHV envelope glycoproteins (gB, ORF28, ORF68, gH, gL, gM, gN and gpK8.1) adsorbed/removed KSHV-specific nAbs from the plasma of infected individuals. Our study revealed that plasma from a majority of KSHV neutralizers recognizes multiple viral glycoproteins. Moreover, the breadth of nAbs responses against these viral glycoproteins varies among endemic KS, epidemic KS and asymptomatic KSHV-infected individuals. Importantly, among the KSHV glycoproteins, the gH/gL complex, but neither gH nor gL alone, showed the highest adsorption of KSHV-specific nAbs. This activity was detected in 80% of the KSHV-infected individuals regardless of their KS status. The findings suggest that the gH/gL complex is the predominant antigenic determinant of KSHV-specific nAbs. Therefore, gH/gL is a potential target for development of KSHV prophylactic vaccines.