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Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma Pinato, David James Kaneko, Takahiro D'Alessio, Antonio Forner, Alejandro Fessas, Petros Mínguez Rosique, Beatriz Giannini, Edoardo G. Grillo, Federica Díaz, Alba Mauri, Francesco A. Fulgenzi, Claudia A.M. Dalla Pria, Alessia Goldin, Robert D. Pieri, Giulia Toniutto, Pierluigi Avellini, Claudio Plaz Torres, Maria Corina Akarca, Ayse U. Marafioti, Teresa Bhoori, Sherrie Miró, Jose María Bower, Mark Bräu, Norbert Mazzaferro, Vincenzo Universitat Autònoma de Barcelona HCC HIV PD-L1 Prognosis HIV-seropositivity shortens survival in patients with hepatocellular carcinoma (HCC). Although risk factors for HCC including HCV infection can influence T cell phenotype, it is unknown whether HIV can influence functional characteristics of the T cell infiltrate. From the Liver Cancer in HIV biorepository, we derived 129 samples of transplanted (76%) or resected (20%) HCC in eight European and North American centres. We profiled intra- and peritumoural tissue to evaluate regulatory CD4+/FOXP3+ and immune-exhausted CD8+/PD1+ T cells in HIV+ (n = 66) and HIV- (n = 63) samples. We performed targeted transcriptomics and T-cell receptor sequencing in a restricted subset of samples evaluated in relationship with HIV status. We correlated immunopathologic features with patients' characteristics including markers of HIV infection. Of the 66 HIV+ patients, 83% were HCV coinfected with an undetectable HIV viral load (51%) and a median blood CD4+ cell count of 430 cells/mm 3 (range 15-908). Patients who were HIV+ were compared with HIV- controls with similar staging characteristics including Barcelona Clinic Liver Cancer (BCLC) stage A-B (86% vs. 83%, p = 0.16), <3 nodules (90% vs. 83%, p = 0.3) and median alpha-foetoprotein values (10.9 vs. 12.8 ng/ml, p = 0.72). HIV+ samples had higher PD-L1 expression rates in tumour tissue (51% vs. 8% p <0.0001) and displayed denser intratumoural CD4+/FOXP3+ (p <0.0001), CD8+/PD1+ (p <0.0001), with lower total peritumoural CD4+ (p <0.0001) and higher peritumoural CD8+/PD1+ (p <0.0001). Gene set analysis revealed HIV+ cases to have evidence of dysregulated adaptive and innate immunity. Tumour-infiltrating lymphocyte clonality was not influenced by HIV status. HIV-associated HCC harbours a profoundly immune-exhausted tumour microenvironment, warranting prospective testing of immunotherapy in this treatment-deprived patient population. Hepatocellular carcinoma is a non-AIDS defining malignancy characterised by poor survival. The programmed cell death (PD-1) pathway governs antiviral and anticancer immune exhaustion and is a therapeutic target in HCC. This study highlights how HIV infection is associated with significantly higher PD-L1 expression in HCC cells and in the surrounding microenvironment, leading to changes in cytotoxic and regulatory T cell function and dysregulation of proinflammatory pathways. Taken together, our results suggest dysfunctional T cell immunity as a mechanism of worse outcome in these patients and suggest clinical testing of checkpoint inhibitors in HIV-associated HCC. 2023 Article https://ddd.uab.cat/record/318127 urn:10.1016/j.jhepr.2023.100741 urn:oai:ddd.uab.cat:318127 urn:pmcid:PMC10238838 urn:pmc-uid:10238838 urn:pmid:37274775 urn:oai:pubmedcentral.nih.gov:10238838 urn:oai:egreta.uab.cat:publications/ee42ad65-7b04-4686-b5ae-a51775dc45b5 eng Instituto de Salud Carlos III PI18/00542 Instituto de Salud Carlos III PI18/00961 Instituto de Salud Carlos III PI21/00714 JHEP Reports ; Vol. 5 (march 2023) open access Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original. https://creativecommons.org/licenses/by/4.0/ application/pdf