We evaluated the impact of the killer immunoglobulin-like receptors (KIR) of natural killer (NK) cells and of their HLA ligands over the clinical outcome of hepatitis C virus (HCV)-related ...hepatocellular carcinoma after curative treatment by either surgical resection or radiofrequency thermal ablation (RTA).
Sixty-one consecutive patients with HCV-related hepatocellular carcinoma underwent KIR genotyping and HLA typing. A phenotypic/functional characterization of NK cells was carried out in patients with different KIR/KIR-ligand genotype.
Activating KIR2DS5 was associated with significantly longer time to recurrence (TTR) and overall survival (OS; P < 0.03 each). Homozygous HLA-C1 (P < 0.02) and HLA-Bw4I80 (P < 0.05) were expressed by patients with significantly better OS, whereas HLA-C2 (P < 0.02) and HLA-Bw4T80 (P < 0.01) were associated with a worse OS. Multivariate analysis identified as parameters independently related to TTR the type of treatment (surgical resection vs. RTA; P < 0.03) and HLA-C1 (P < 0.03), whereas only KIR2DS5 was an independent predictor of longer OS (P < 0.05). Compound KIR2DL2-C1 and KIR3DS1-Bw4T80 genotypes were associated with better TTR (P < 0.03) and worse OS (P = 0.02), respectively. A prevalent cytotoxic (CD56(dim)) NK phenotype was detected in patients with both longer TTR and OS. Cytotoxic capacity measured by upregulation of CD107a was significantly higher in subjects with HLA-C1 alone or combined with KIR2DL2/KIR2DL3.
These results support a central role of NK cells in the immune response against hepatocellular carcinoma, providing a strong rationale for therapeutic strategies enhancing NK response and for individualized posttreatment monitoring schemes.
Natural killer (NK) cells may become functionally exhausted entering hepatocellular carcinoma (HCC), and this has been associated with tumor progression and poor clinical outcome. Hypoxia, low ...nutrients, immunosuppressive cells, and soluble mediators characterize the intratumor microenvironment responsible for the metabolic deregulation of infiltrating immune cells such as NK cells. HCC-infiltrating NK cells from patients undergoing liver resection for HCC were sorted, and genome-wide transcriptome profiling was performed. We have identified a marked general upregulation of gene expression profile along with metabolic impairment of glycolysis, OXPHOS, and autophagy as well as functional defects of NK cells. Targeting p38 kinase, a stress-responsive mitogen-activated protein kinase, we could positively modify the metabolic profile of NK cells with functional restoration in terms of TNF-α production and cytotoxicity. We found a metabolic and functional derangement of HCC-infiltrating NK cells that is part of the immune defects associated with tumor progression and recurrence. NK cell exhaustion due to the hostile tumor microenvironment may be restored with p38 inhibitors with a selective mechanism that is specific for tumor-infiltrating-not affecting liver-infiltrating-NK cells. These results may represent the basis for the development of a new immunotherapeutic strategy to integrate and improve the available treatments for HCC.
The definition of the risk of hepatocellular carcinoma (HCC) recurrence after resection represents a central issue to improve the clinical management of patients. In this study we examined the ...prognostic relevance of infiltrating immune cell subsets in the tumor (TIL) and in nontumorous (NT) liver (LIL), and the expression of immune-related and lineage-specific mRNAs in HCC and NT liver derived from 42 patients. The phenotype of infiltrating cells was analyzed by flow cytometry, and mRNA expression in liver tissue was examined by real-time reverse transcription (RT)-PCR. The tumor immune microenvironment was enriched in inhibitory and dysfunctional cell subsets. Enrichment in CD4+ T-cells and in particular CD4 and CD8+ memory subsets within TIL was predictive of better overall survival (OS) and time to recurrence (TTR). Increased programmed death ligand 1 (PDL1) mRNA content and higher prevalence of invariant NKT (iNKT) cells were associated with shorter OS and TTR, respectively. By combined evaluation of infiltrating cell subsets along with mRNA profiling of immune and tumor related genes, we identified the intratumoral frequency of memory T-cells and iNKT-cells as well as PDL1 expression as the best predictors of clinical outcome. HCC infiltrate is characterized by the expression of molecules with negative regulatory function that may favor tumor recurrence and poor survival.
Previous studies support the role of natural killer (NK) cells in controlling hepatocellular carcinoma (HCC) progression. However, ambiguity remains about the multiplicity and the role of different ...NK cell subsets, as a pro-oncogenic function has been suggested. We performed phenotypic and functional characterization of NK cells infiltrating HCC, with the corresponding nontumorous tissue and liver from patients undergoing liver resection for colorectal liver metastasis used as controls. We identified a reduced number of NK cells in tumors with higher frequency of CD56
CD16
NK cells associated with higher expression of NKG2A, NKp44, and NKp30 and downregulation of NKG2D. Liver-resident (CXCR6
) NK cells were reduced in the tumors where T-bet
Eomes
expression was predominant. HCCs showed higher expression of CD49a with particular enrichment in CD49a
Eomes
NK cells, a subset typically represented in the decidua and playing a proangiogenic function. Functional analysis showed reduced TNF-α production along with impaired cytotoxic capacity that was inversely related to CXCR6
, T-bet
Eomes
, and CD49a
Eomes
NK cells. In conclusion, we identified a subset of NK cells infiltrating HCC, including non-liver-resident cells that coexpressed CD49a and Eomes and showed reduced cytotoxic potential. This NK cell subset likely plays a regulatory role in proangiogenic function.
Transarterial chemoembolization (TACE) is one of the most frequently applied treatments for hepatocellular carcinoma (HCC) worldwide. In this study, we aimed at evaluating whether and how TACE ...application and repetition, as well as the related outcome, have changed over the last three decades in Italy.
Data of 7,184 patients with HCC were retrieved from the Italian Liver Cancer (ITA.LI.CA) database. Patients were divided according to the period of diagnosis in six cohorts: P1 (1988-1993), P2 (1994-1998), P3 (1999-2004), P4 (2005-2009), P5 (2010-2014), and P6 (2015-2019). All the analyses were repeated in the overall patient population and in Barcelona Clinic Liver Cancer (BCLC) B patients, who are the subgroup of HCC patients originally supposed to receive TACE according to guidelines. TACE was defined as either the first or the main (more effective) treatment.
The proportion of patients receiving TACE as first or main therapy declined over time, and less than 50% of BCLC B patients were treated with chemoembolization from P3 onward. Conversely, TACE was widely used even outside the intermediate stage. Survival of TACE-treated patients progressively increased from P1 to P6. Although TACE was performed only once in the majority of patients, there was an increasing proportion of those receiving 2 or ≥3 treatments sessions over time. The overall survival (OS) of patients undergoing repeated treatments was significantly higher compared to those managed with a single TACE (median OS 40.0 vs. 65.0 vs. 71.8 months in 1, 2, and ≥3 TACE groups, respectively; p < 0.0001). However, after a first-line TACE, the adoption of curative therapies provided longer survival than repeating TACE (83.0 vs. 42.0 months; p < 0.0001), which in turn was associated with better outcomes compared to systemic therapies or best supportive care (BSC).
Despite a decline in the percentage of treated patients over time, TACE has still an important role in the management of HCC patients. The survival of TACE-treated patients gradually improved over time, probably due to a better patient selection. Iterative TACE is effective, but an upward shift to curative therapies provides better outcomes while transition to systemic therapies and BSC leads to a worse prognosis.
We aimed at assessing the impact of surveillance on long-term survival in HCC patients.
From the ITA.LI.CA database, we selected 1028 cases with long (≥5 years, LS group) and 2721 controls with ...short-term survival (<5 years, SS group). The association between surveillance and LS was adjusted for confounders by multivariable logistic regression analysis. Survival of surveilled patients was presented both as observed and corrected for the lead-time bias, and the comparison of survival between surveillance and no surveillance groups was also performed after balancing the baseline characteristics with inverse probability weights (IPW).
LS patients were more frequently diagnosed under surveillance (
< 0.0001), and had more favorable baseline characteristics. Surveillance was an independent predictor of LS (OR = 1.413, 95% CI 1.195-1.671;
< 0.0001). The observed and the lead-time corrected survival of surveilled patients were significantly longer compared to the survival of not surveilled patients (
< 0.0001 and
= 0.0008, respectively). In IPW adjusted populations, no survival differences were demonstrated between the two groups (
= 0.30).
Surveillance, increasing early-stage diagnosis and applicability of curative treatments, is a fundamental determinant of long-term survival in HCC patients. A wide implementation of surveillance programs should be pursued in order to improve HCC patients' prognosis.
Alcohol abuse and metabolic disorders are leading causes of hepatocellular carcinoma (HCC) worldwide. Alcohol-related aetiology is associated with a worse prognosis compared with viral agents, ...because of the lower percentage of patients diagnosed with HCC under routine surveillance and a higher burden of comorbidity in alcohol abusers. This study aimed to describe the evolving clinical scenario of alcohol-related HCC over 15 years (2006–2020) in Italy.
Data from the Italian Liver Cancer (ITA.LI.CA) registry were used: 1,391 patients were allocated to three groups based on the year of HCC diagnosis (2006–2010; 2011–2015; 2016–2020). Patient characteristics, HCC treatment, and overall survival were compared among groups. Survival predictors were also investigated.
Approximately 80% of alcohol-related HCCs were classified as cases of metabolic dysfunction-associated fatty liver disease. Throughout the quinquennia, <50% of HCCs were detected by surveillance programmes. The tumour burden at diagnosis was slightly reduced but not enough to change the distribution of the ITA.LI.CA cancer stages. Intra-arterial and targeted systemic therapies increased across quinquennia. A modest improvement in survival was observed in the last quinquennia, particularly after 12 months of patient observation. Cancer stage, HCC treatment, and presence of oesophageal varices were independent predictors of survival.
In the past 15 years, modest improvements have been obtained in outcomes of alcohol-related HCC, attributed mainly to underuse of surveillance programmes and the consequent low amenability to curative treatments. Metabolic dysfunction-associated fatty liver disease is a widespread condition in alcohol abusers, but its presence did not show a pivotal prognostic role once HCC had developed. Instead, the presence of oesophageal varices, an independent poor prognosticator, should be considered in patient management and refining of prognostic systems.
Alcohol abuse is a leading and growing cause of hepatocellular carcinoma (HCC) worldwide and is associated with a worse prognosis compared with other aetiologies. We assessed the evolutionary landscape of alcohol-related HCC over 15 years in Italy. A high cumulative prevalence (78%) of metabolic dysfunction-associated fatty liver disease, with signs of metabolic dysfunction, was observed in HCC patients with unhealthy excessive alcohol consumption. The alcohol + metabolic dysfunction-associated fatty liver disease condition tended to progressively increase over time. A modest improvement in survival occurred over the study period, likely because of the persistent underuse of surveillance programmes and, consequently, the lack of improvement in the cancer stage at diagnosis and the patients’ eligibility for curative treatments. Alongside the known prognostic factors for HCC (cancer stage and treatment), the presence of oesophageal varices was an independent predictor of poor survival, suggesting that this clinical feature should be carefully considered in patient management and should be included in prognostic systems/scores for HCC to improve their performance.
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•Alcohol-related HCC is increasing in incidence and has a poor prognosis.•Signs of metabolic dysfunction are present in most patients with HCC.•The rate of alcohol-related HCC diagnosed by ultrasound surveillance is <50%.•Only a modest survival improvement has been achieved in the last 15 years.•Cancer stage, oesophageal varices, and treatment were predictors of survival.
Metabolic dysfunction-associated fatty liver disease (MAFLD) represents a new inclusive definition of the whole spectrum of liver diseases associated to metabolic disorders. The main objective of ...this study was to compare patients with MAFLD and non-MAFLD with hepatocellular carcinoma (HCC) included in a nationally representative cohort.
We analysed 6882 consecutive patients with HCC enrolled from 2002 to 2019 by 23 Italian Liver Cancer centres to compare epidemiological and future trends in three subgroups: pure, single aetiology MAFLD (S-MAFLD); mixed aetiology MAFLD (metabolic and others, M-MAFLD); and non-MAFLD HCC.
MAFLD was diagnosed in the majority of patients with HCC (68.4%). The proportion of both total MAFLD and S-MAFLD HCC significantly increased over time (from 50.4% and 3.6% in 2002-2003, to 77.3% and 28.9% in 2018-2019, respectively, p<0.001). In Italy S-MAFLD HCC is expected to overcome M-MAFLD HCC in about 6 years. Patients with S-MAFLD HCC were older, more frequently men and less frequently cirrhotic with clinically relevant portal hypertension and a surveillance-related diagnosis. They had more frequently large tumours and extrahepatic metastases. After weighting, and compared with patients with non-MAFLD, S-MAFLD and M-MAFLD HCC showed a significantly lower overall (p=0.026, p=0.004) and HCC-related (p<0.001, for both) risk of death. Patients with S-MAFLD HCC showed a significantly higher risk of non-HCC-related death (p=0.006).
The prevalence of MAFLD HCC in Italy is rapidly increasing to cover the majority of patients with HCC. Despite a less favourable cancer stage at diagnosis, patients with MAFLD HCC have a lower risk of HCC-related death, suggesting reduced cancer aggressiveness.
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