The study aims to analyze blood samples from patients with advanced hepatocellular carcinoma who are receiving systemic treatment with immunotherapy. The objective is to determine whether treatment exposure leads to changes in the transcriptomic patterns of peripheral blood mononuclear cells (PBMCs), if these changes are associated with treatment response, and whether certain pre-treatment transcriptomic signatures can predict response to treatment.

As an exploratory objective, PBMCs derived from patients exposed to immune checkpoint inhibitors will be co-cultured with their paired tumor cells in organoid cultures. This aims to assess whether these preclinical 3D models correlate with clinical outcomes.

The primary pivotal objective of the study is to analyse the single cell transcriptome of peripheral blood mononuclear cells (PBMCs) in patients with HCC treated with immunotherapy to define if treatment exposure determines transcriptomic pattern changes and if some of these changes are associated with treatment response.

The secondary objective of the study is to investigate if some pre-treatment transcriptome signature of PBMCs is predictive of response and long-lasting response to treatment.

As an exploratory objective, the study investigators will analyse the interaction between patients' peripheral immune cells previously exposed to immune check-point inhibitors and their paired tumour cells in the organoid cultures.

Inclusion Criteria:

1. diagnosis of advanced HCC treated with atezolizumab plus bevacizumab or tremelimumab single dose plus durvalumab (STRIDE regimen) as first-line treament
2. age ≥18 and <90 years at time of signing informed consent
3. Signed Informed Consent Form

Exclusion Criteria:

1. Life expectancy of <12 months due to concomitant diseases

2. Active or history of autoimmune disease or immune deficiency on inflammatory chronic diseases

3. Ongoing drug abuse

4. History of malignancy other than HCC within 3 years prior to study entry with the following exception:

   1. Completely resected malignancies with a negligible risk of metastasis or death (e.g., 5-year OS rate 90%) and without evidence of recurrence for > 3 years prior to study entry
   2. adequately treated non-melanoma skin carcinoma or lentigo maligna without evidence of metastases.
   3. adequately treated carcinoma in situ of the cervix without evidence of recurrence
   4. localised prostate cancer
   5. adequately treated non invasive or in situ urothelial cancers

5. evidence or history of positive HIV test

6. inability to comply with the study protocol, in the investigator's judgment

Patients treated with atezolizumab plus bevacizumab or tremelimumab single dose plus durvalumab (STRIDE regimen) as first-line treament for advanced HCC

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