---
title: "HHV-8 expression shapes the tumour microenvironment in HIV-associated and classic Kaposi sarcoma"
id: "british-journal-of-cancer-0-in-depth-characterisation-of-the-tumour-microenvironment-reveals-hhv-8"
canonical_url: "https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-in-depth-characterisation-of-the-tumour-microenvironment-reveals-hhv-8"
content_type: "clinical_feed_article"
specialty: "Oncology"
source_name: "British Journal of Cancer"
source_url: "https://www.nature.com/articles/s41416-026-03536-5"
published_at: "2026-08-05T09:49:38.000Z"
evidence_level: "Journal Feed"
license: "CC-BY-NC-4.0 / Informational Use"
---
# HHV-8 expression shapes the tumour microenvironment in HIV-associated and classic Kaposi sarcoma
## Provenance & Clinical Metadata
- **Canonical URL:** https://medichelpline.com/clinical-feed/british-journal-of-cancer-0-in-depth-characterisation-of-the-tumour-microenvironment-reveals-hhv-8
- **Specialty:** [Oncology](https://medichelpline.com/clinical-feed/oncology.md)
- **Primary Source:** British Journal of Cancer
- **Source URL:** [Original Journal Publication](https://www.nature.com/articles/s41416-026-03536-5)
- **Published At:** 2026-08-05T09:49:38.000Z
- **Evidence Rating:** Journal Feed
## Executive GIST (TL;DR)
- This study compared clinical features and the **tumour microenvironment (TME)** of 21 HIV-associated Kaposi sarcoma (KS) cases with well-controlled HIV and 19 non-HIV-associated (classic) KS cases using targeted transcriptomics and multiplex immunofluorescence on archival tissue. - All HIV-associated patients were on combined antiretroviral therapy (**cART**) ≥3 months, had HIV-RNA 200 cells/mm3; non-controlled HIV and other causes of immunosuppression were excluded. - Clinical outcomes, including progression-free survival (PFS), were similar between the two cohorts after a median follow-up of 15.3 months; median PFS in the whole cohort was 17.3 months. - The **TME** of non-HIV-associated (classic) KS showed transcriptional upregulation of pathways linked to **adaptive and innate immunity** and **angiogenesis** compared with HIV-associated KS. - HIV-associated KS tumours demonstrated lower infiltration of activated **CD4** cells and a lower degree of inflammation with more pronounced epithelial-to-mesenchymal transition features compared with classic KS. - Across both cohorts, intra-tumoral **HHV-8** gene expression positively correlated with markers of activated **CD4**, **CD8**, **NK** cells and **immune checkpoint** gene expression, indicating viral gene expression as a driver of TME composition. - Methods: RNA from FFPE tumour blocks was profiled with the NanoString nCounter PanCancer IO 360 Panel plus a custom 10-gene HHV-8 CodeSet; multiplex immunofluorescence used two 6-marker panels on 12 FFPE blocks; plasma HHV-8 DNA was quantified by nested PCR targeting ORF26. - Clinical sampling, ethics approvals, and sample processing were described; some analytic details and full methods are reported in supplementary materials referenced by the source. - The authors conclude that even with well-controlled HIV infection, KS TMEs differ from non-HIV KS, and intratumoral **HHV-8** expression is associated with immune cell infiltration and checkpoint expression, with implications for immunotherapy strategies in KS.
## Clinical Analysis & Structured Key Points
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[nature](https://www.nature.com/) 2. [british journal of cancer](https://www.nature.com/bjc) 3. [articles](https://www.nature.com/bjc/articles?type=article) 4. article In-depth characterisation of the tumour microenvironment reveals HHV-8-dependent immune regulation in HIV-associated and classic Kaposi sarcoma [ Download PDF ](https://www.nature.com/articles/s41416-026-03536-5.pdf) [ Download PDF ](https://www.nature.com/articles/s41416-026-03536-5.pdf) * Article * [Open access](https://www.springernature.com/gp/open-science/about/the-fundamentals-of-open-access-and-open-research) * Published: 05 August 2026 Translational Therapeutics # In-depth characterisation of the tumour microenvironment reveals HHV-8-dependent immune regulation in HIV-associated and classic Kaposi sarcoma * [Claudia A. M. Fulgenzi](https://www.nature.com/articles/s41416-026-03536-5#auth-Claudia_A__M_-Fulgenzi-Aff1)[1](https://www.nature.com/articles/s41416-026-03536-5#Aff1) [na1](https://www.nature.com/articles/s41416-026-03536-5#na1), * [Alessia Dalla Pria](https://www.nature.com/articles/s41416-026-03536-5#auth-Alessia-Dalla_Pria-Aff2-Aff3)[2](https://www.nature.com/articles/s41416-026-03536-5#Aff2),[3](https://www.nature.com/articles/s41416-026-03536-5#Aff3) [na1](https://www.nature.com/articles/s41416-026-03536-5#na1), * [Yiran Zhao](https://www.nature.com/articles/s41416-026-03536-5#auth-Yiran-Zhao-Aff1)[1](https://www.nature.com/articles/s41416-026-03536-5#Aff1), * [Alberto Giovanni Leone](https://www.nature.com/articles/s41416-026-03536-5#auth-Alberto_Giovanni-Leone-Aff4)[4](https://www.nature.com/articles/s41416-026-03536-5#Aff4), * [Justin Weir](https://www.nature.com/articles/s41416-026-03536-5#auth-Justin-Weir-Aff5)[5](https://www.nature.com/articles/s41416-026-03536-5#Aff5), * [Ignazio Puccio](https://www.nature.com/articles/s41416-026-03536-5#auth-Ignazio-Puccio-Aff1)[1](https://www.nature.com/articles/s41416-026-03536-5#Aff1), * [Krista S. Tuohinto](https://www.nature.com/articles/s41416-026-03536-5#auth-Krista_S_-Tuohinto-Aff6)[6](https://www.nature.com/articles/s41416-026-03536-5#Aff6), * [Päivi M. Ojala](https://www.nature.com/articles/s41416-026-03536-5#auth-P_ivi_M_-Ojala-Aff6)[6](https://www.nature.com/articles/s41416-026-03536-5#Aff6), * [Mark Bower](https://www.nature.com/articles/s41416-026-03536-5#auth-Mark-Bower-Aff2)[2](https://www.nature.com/articles/s41416-026-03536-5#Aff2) & * … * [David J. Pinato](https://www.nature.com/articles/s41416-026-03536-5#auth-David_J_-Pinato-Aff1-Aff7) [ORCID: orcid.org/0000-0002-3529-0103](https://orcid.org/0000-0002-3529-0103)[1](https://www.nature.com/articles/s41416-026-03536-5#Aff1),[7](https://www.nature.com/articles/s41416-026-03536-5#Aff7) Show authors [_British Journal of Cancer_](https://www.nature.com/bjc) (2026) [Cite this article](https://www.nature.com/articles/s41416-026-03536-5#citeas) [ Save article ](https://www.nature.com/articles/s41416-026-03536-5/save-research?_csrf=EAViOqFAJKIa_yb8ASb5at0IPeY-CJMp) [ View saved research ](https://www.nature.com/saved-research) ## Abstract ### Background Kaposi’s sarcoma (KS) is the most common malignancy occurring in people living with HIV (PLWH). The clinical course of KS in PLWH established on combined anti-retroviral therapy (cART) resembles that of classic KS. ### Objectives To compare the clinical and biological characteristics of HIV-associated KS in patients with well-controlled viral infection (_N_ = 21) and non-HIV-associated KS (_N_ = 19). ### Methods Clinical data were prospectively collected from patients treated at the National Centre for HIV malignancies at Chelsea & Westminster Hospital. Targeted transcriptomic analysis and multiplex immune-fluorescence were performed on archival tumour samples. ### Results Clinical outcomes were comparable between groups. The tumour microenvironment (TME) of non-HIV-associated KS was characterised by transcriptional upregulation of pathways associated with adaptive and innate immunity and angiogenesis. The TME of HIV-associated cases was associated with lower infiltration of activated CD4 cells. In both cohorts, we found the expression of HHV-8 genes to positively correlate with activated CD4, CD8, NK and immune checkpoint gene expression. ### Conclusions The KS TME in the presence of well-controlled HIV infection is characterised by a lower degree of inflammation and more pronounced epithelial to mesenchymal transition. We also identified intra-tumoral HHV-8 gene expression as a driver of TME composition. ## Introduction Kaposi’s sarcoma (KS) is a mesenchymal tumour of possible lymphovascular origin that recognises Human Herpes Virus 8 (HHV-8) infection as the necessary but not sufficient pathogenic mechanism [[1](https://www.nature.com/articles/s41416-026-03536-5#ref-CR1 "Mariggio G, Koch S, Schulz TF. Kaposi sarcoma herpesvirus pathogenesis. Philos Trans R Soc Lond B Biol Sci. 2017;372:20160275.")]. Uncontrolled HIV infection represents one of the most common causes of KS development and progression [[2](https://www.nature.com/articles/s41416-026-03536-5#ref-CR2 "Guihot A, Dupin N, Marcelin AG, Gorin I, Bedin AS, Bossi P, et al. Low T cell responses to human herpesvirus 8 in patients with AIDS-related and classic Kaposi sarcoma. J Infect Dis. 2006;194:1078–88.")] and, despite the drop in its incidence after the introduction of combined-anti-retroviral therapy (cART), KS remains the most common malignancy in people living with HIV (PLWH). The current taxonomic classification of KS recognises classic, iatrogenic, epidemic, endemic and KS in men who have sex with men as five independent classes based on disease epidemiology. Recent evidence from our group has emphasised that the degree of baseline immune suppression, independently of the cause, is the main factor influencing the clinical course of KS [[3](https://www.nature.com/articles/s41416-026-03536-5#ref-CR3 "Openshaw MR, Gervasi E, Fulgenzi CAM, Pinato DJ, Dalla Pria A, Bower M. Taxonomic reclassification of Kaposi Sarcoma identifies disease entities with distinct immunopathogenesis. J Transl Med. 2023;21:283.")], and reducing the degree of immune suppression leads to KS remission. For instance, while formally included in the ‘epidemic’ group, HIV-associated KS includes clinical entities occurring in the presence of well-controlled HIV, resembling more closely that of classic KS rather than that of AIDS-associated KS. Equally, iatrogenic KS often has a clinical course that mimics that of AIDS-associated KS rather than other forms of KS [[3](https://www.nature.com/articles/s41416-026-03536-5#ref-CR3 "Openshaw MR, Gervasi E, Fulgenzi CAM, Pinato DJ, Dalla Pria A, Bower M. Taxonomic reclassification of Kaposi Sarcoma identifies disease entities with distinct immunopathogenesis. J Transl Med. 2023;21:283.")]. In the case of KS persistence or recurrence, or when the underlying immune suppression cannot be treated, chemotherapy is effectively used to treat KS [[4](https://www.nature.com/articles/s41416-026-03536-5#ref-CR4 "Dalla Pria A, Pinato DJ, Bracchi M, Bower M. Recent advances in HIV-associated Kaposi sarcoma. F1000Research. 2019;8:F1000-aculty.")]. However, while immunosuppression remains key for KS development and progression, little is known about the biologic and immunologic characteristics of KS occurring in the absence of clinically significant immune suppression. The strong pathogenic reliance of KS upon defective adaptive immunity makes the use of immunotherapy particularly appealing in this malignancy. So far, immune checkpoint inhibitors have shown promising efficacy in both classic and HIV-associated KS [[5](https://www.nature.com/articles/s41416-026-03536-5#ref-CR5 "Rajdev L, Jackie Wang CC, Joshi H, Lensing S, Lee J, Ramos JC, et al. Assessment of the safety of nivolumab in people living with HIV with advanced cancer on antiretroviral therapy: the AIDS Malignancy Consortium 095 Study. Cancer. 2024;130:985–94."), [6](https://www.nature.com/articles/s41416-026-03536-5#ref-CR6 "Delyon J, Biard L, Renaud M, Resche-Rigon M, Le Goff J, Dalle S, et al. PD-1 blockade with pembrolizumab in classic or endemic Kaposi’s sarcoma: a multicentre, single-arm, Phase 2 study. Lancet Oncol. 2022;23:491–500.")], with an objective response rate reaching 87% for the combination of ipilimumab (anti-CTLA-4) plus nivolumab (anti-PD-1) in classic KS [[7](https://www.nature.com/articles/s41416-026-03536-5#ref-CR7 "Zer A, Icht O, Yosef L, Avram D, Jacobi O, Fenig E, et al. Phase II single-arm study of nivolumab and ipilimumab \(Nivo/Ipi\) in previously treated classical Kaposi sarcoma \(cKS\). Ann Oncol. 2022;33:720–7.")]. Similarly, immunomodulatory agents such as pomalidomide have shown anti-cancer activity in both HIV and non-HIV-associated cases [[8](https://www.nature.com/articles/s41416-026-03536-5#ref-CR8 "Polizzotto MN, Uldrick TS, Wyvill KM, Aleman K, Peer CJ, Bevans M, et al. Pomalidomide for symptomatic Kaposi’s sarcoma in people with and without HIV infection: a Phase I/II study. J Clin Oncol. 2016;34:4125–31.")]. A better understanding of the biologic mechanisms leading to KS in the absence of clinically significant immune suppressions remains pivotal to develop new treatment strategies. In this study, we aimed to investigate the differences between HIV-associated KS occurring in the presence of well-controlled HIV infection and non-HIV-associated KS without clinically evident immune suppression, by comparing the clinical characteristics and the composition of the tumour microenvironment (TME) of two matched cohorts. ## Methods ### Patient population The two study cohorts were selected from a prospectively maintained dataset including all patients treated at the National Centre for HIV malignancies at the Chelsea and Westminster Hospital. The study included 40 consecutive patients with histology-proven KS diagnosed from 01/2008 to 02/2015 and available tissue samples. Diagnostic tissue was retrieved from the pathology archive. Patients with non-controlled HIV, defined as viral load >200 copies/ml and CD4 count 200 cells/mm3. The baseline characteristics of the whole cohort and the two main subgroups are summarised in Table [1](https://www.nature.com/articles/s41416-026-03536-5#Tab1). In brief, most of the patients were males (_N_ = 37), 24 out of 40 had prior loco-regional therapies to treat KS, with excision being the most common (_N_ = 17); 22 received at least one line of systemic therapy. A higher proportion of non-HIV-associated cases received loco-regional treatments (73.7 vs 43.5%, Chi-squared test, _p_ = 0.049). The proportion of patients requiring at least one line of systemic therapy was not significantly different between HIV-associated and non-HIV-associated cases (62.5 vs 42.1%, Chi-squared test, _p_ = 0.183). Among patients who received systemic therapy, doxorubicin-based formulations were used as first-line treatment in 14 out of 15 (93.3%) patients in the HIV_associated cohort, and 8 out of 8 patients in the non-HIV-associated cohort (100%). As expected, people with high-risk KS were more likely to receive systemic therapy compared to low-risk patients (93.3 vs 33.3%). The median time from first KS diagnosis (either clinical or histology proven) and the last histology confirming KS (referred to the tissue used for the translational analysis of this study) was 6.8 months (range: 0–21 years). In those requiring systemic therapy, all the samples were collected prior to the start of the last line of treatment. As reported in Table [1](https://www.nature.com/articles/s41416-026-03536-5#Tab1), patients with HIV-associated KS had a younger age at first diagnosis, higher peripheral blood CD8 count and lower HHV-8 levels. Other baseline characteristics were well-balanced across the 2 cohorts. After a median follow-up of 15.3 months (95% CI: 12.0–30.3), median PFS in the whole cohort was 17.3 months (95% CI: 8.0–NA, Supplementary Fig. [1A](https://www.nature.com/articles/s41416-026-03536-5#MOESM1)), which was not different when stratified according to the HIV status (HR = 1.3; 95% CI: 0.50–3.48, _p_ = 0.6, Supplementary Fig. [1B](https://www.nature.com/articles/s41416-026-03536-5#MOESM1)). Two patients (9.5%) in the HIV-associated cohort had a past medical history of multicentric Castleman’s disease (CD), which is
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