Background & Aims
HIV-seropositivity shortens survival in patients with hepatocellular carcinoma (HCC). Whilst risk factors for HCC including Hepatitis C virus 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 8 European and North American centres. We profiled intra and peri-tumoural 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 immuno-pathologic features with patients’ characteristics including markers of HIV infection.

Results
Of the 66 HIV+ patients, 83% were Hepatitis C virus co-infected with an undetectable HIV viral load (51%) and a median blood CD4+ cell count of 430 cells/mm3 (range 15-908). HIV+ patients 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 alfa-fetoprotein (AFP) 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 a denser intra-tumoral CD4+/FOXP3+ (p<0.0001), CD8+/PD1+ (p<0.0001), with lower total peri-tumoral CD4+ (p<0.0001) and higher peri-tumoral 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.