Integrated phenotyping of the anti-cancer immune response in HIV-associated hepatocellular carcinoma
David J. Pinato,
Takahiro Kaneko,
Antonio D’Alessio,
Alejandro Forner,
Petros Fessas,
Beatriz Minguez,
Edoardo G. Giannini,
Federica Grillo,
Alba Díaz,
Francesco A. Mauri,
Claudia A.M. Fulgenzi,
Alessia Dalla Pria,
Robert D. Goldin,
Giulia Pieri,
Pierluigi Toniutto,
Claudio Avellini,
Maria Corina Plaz Torres,
Ayse U. Akarca,
Teresa Marafioti,
Sherrie Bhoori,
Jose María Miró,
Mark Bower,
Norbert Bräu,
Vincenzo Mazzaferro
Affiliations
David J. Pinato
Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy; Corresponding author. Address: Imperial College London Hammersmith Campus, Du Cane Road, W12 0HS, London, UK. Tel.: +44-20-8383-3720
Takahiro Kaneko
Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Tokyo Medical and Dental University, Tokyo, Japan
Antonio D’Alessio
Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Division of Oncology, Department of Translational Medicine, University of Piemonte Orientale, Novara, Italy
Alejandro Forner
Liver Unit, Barcelona Clinic Liver Cancer (BCLC) Group, ICMDM, Hospital Clinic Barcelona, IDIBAPS. University of Barcelona, Barcelona, Spain; National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain
Petros Fessas
Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK
Beatriz Minguez
Liver Unit, Department of Internal Medicine Hospital Universitari Vall d’Hebron, Universitat Autonoma de Barcelona, Barcelona, Spain; Vall d’Hebron Institute of Research (VHIR), CIBERehd Vall d’Hebron, Barcelona Hospital Campus, Barcelona, Spain
Edoardo G. Giannini
Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS-Ospedale Policlinico San Martino, Genoa, Italy
Federica Grillo
Pathology Unit, Department of Surgical Sciences and Integrated Diagnostics, University of Genoa, IRCCS-Ospedale Policlinico San Martino, Genoa, Italy
Alba Díaz
National Biomedical Research Institute on Liver and Gastrointestinal Diseases (CIBEREHD), Instituto de Salud Carlos III, Madrid, Spain; Pathology Department, Hospital Clínic, University of Barcelona, Barcelona, Catalonia, Spain
Francesco A. Mauri
Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK
Claudia A.M. Fulgenzi
Department of Surgery & Cancer, Imperial College London, Hammersmith Hospital, Du Cane Road, London, UK; Medical Oncology Department, Fondazione Policlinico Universitario Campus Bio-Medico, Rome, Italy
Alessia Dalla Pria
National Centre for HIV Malignancy, Department of Oncology, Chelsea & Westminster Hospital, London, UK
Robert D. Goldin
Centre for Pathology, Imperial College London, London, UK
Giulia Pieri
Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS-Ospedale Policlinico San Martino, Genoa, Italy
Pierluigi Toniutto
Hepatology and Liver Transplantation Unit, Department of Medical Area (DAME), University of Udine, Udine, Italy
Claudio Avellini
Azienda Ospedaliero-Universitaria “Santa Maria della Misericordia”, Institute of Histopathology, Udine, Italy
Maria Corina Plaz Torres
Gastroenterology Unit, Department of Internal Medicine, University of Genoa, IRCCS-Ospedale Policlinico San Martino, Genoa, Italy
Ayse U. Akarca
Department of Histopathology, University College London Hospital, London, UK
Teresa Marafioti
Department of Histopathology, University College London Hospital, London, UK
Sherrie Bhoori
Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy
Jose María Miró
Department of Infectious Disease, Hospital Clinic-IDIBAPS, University of Barcelona, Barcelona, Spain; CIBERINFEC, Instituto de Salud Carlos III, Madrid, Spain
Mark Bower
National Centre for HIV Malignancy, Department of Oncology, Chelsea & Westminster Hospital, London, UK
Norbert Bräu
James J. Peters VA Medical Center, Bronx, New York, NY, USA; Icahn School of Medicine at Mount Sinai, New York, NY, USA
Vincenzo Mazzaferro
Hepato-Pancreatic-Biliary Surgery and Liver Transplantation, Fondazione IRCCS Istituto Nazionale Tumori, Milan, Italy; Department of Oncology, University of Milan, Milan, Italy
Background & Aims: 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. Methods: 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. Results: 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/mm3 (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. Conclusions: HIV-associated HCC harbours a profoundly immune-exhausted tumour microenvironment, warranting prospective testing of immunotherapy in this treatment-deprived patient population. Impact and Implications: 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.
