Carregant...
Fitxers
Tipus de document
TesiVersió
Versió publicadaData de publicació
Llicència de publicació
Si us plau utilitzeu sempre aquest identificador per citar o enllaçar aquest document: https://hdl.handle.net/2445/207980
Immunogenomic characterization of HCC and etiology-dependent response to immunotherapies
Títol de la revista
Autors
Director/Tutor
ISSN de la revista
Títol del volum
Resum
[eng] INTRODUCTION: Liver cancer is a devastating disease and represents the seventh most common cancer worldwide and the third leading cause of cancer-related death globally. Hepatocellular carcinoma accounts for 90% of all primary liver cancer cases and it is a heterogeneous disease with various etiological factors. It is estimated that around 50- 60% of HCC patients will be exposed to systemic therapies in their lifespan, particularly in advanced stages of the disease. Molecular profiling of HCC, with genome-wide analysis, DNA methylation and mRNA expression profiles analysis, has significantly contributed to the understanding on the molecular pathogenesis of this disease. In recent years, the immune classification of HCC allowed the identification of 25% of patients who belonged to the immune class. That subset of patients was characterized by a high immune infiltration and molecular features resembling melanoma patients responding to ICIs. However, the immune traits of the remaining 75% of patients who did not belong to the immune class, were poorly characterized.
It should be further noted that several things must be considered regarding patient management and treatment allocation. Currently, they are based on BCLC classification, that includes prognostic variables related to tumor status, liver function and health performance status along with treatment-dependent variables obtained from cohort studies and randomized trials. In this regard, the only biomarker- guided therapy for HCC is ramucirumab, which is used as second-line therapy in those patients presenting α-fetoprotein levels ≥400ng/ml [105]. Furthermore, etiology is not considered relevant when deciding the best treatment option for the patient with advanced HCC. Additionally, 25% of all HCCs present with potentially actionable mutations, which are yet to be translated into the clinical practice. At present, the combination of atezolizumab/bevacizumab has recently become the new standard of care in first line, since it was the first regimen to improve OS compared with sorafenib.
This combination therapy showed the highest rate of objective response (~30%) when compared to all other HCC available therapies (ORR for nivolumab was 15-20%, and ORR for sorafenib was ~10%). This gives a total of ~70% of patients that, for different reasons (primary or adaptive resistance) will be refractory to the currently available therapies.
There is, therefore, a critical need to identify mechanisms predisposing patients to present resistance to immunotherapies, therapeutic strategies to overcome such resistance, and to find biomarkers that could be able to predict response/resistance to immunotherapies.
HYPOTHESIS:
Considering all this, the hypotheses of this thesis are that:
1. Performing a comprehensive understanding of the immunomolecular and genomic features of HCC tumors could potentially lead to the discovery of effective biomarkers of response to immune-based therapies and identify novel targets leading to the design of rationale therapeutic strategies.
2. Comparing the clinical responses of NASH and non-NASH related HCC patients to ICIs would lead to identify the role of the etiology in these types of treatments.
AIMS:
Considering the background and hypotheses exposed above, the specific aims of this doctoral thesis were the following:
The main aims of the current doctoral were:
1. Establish an immunogenomic classification of HCC, by integrating features of tumor microenvironment and tumor molecular traits, capable of identifying different mechanisms governing immune response and mechanisms of immune exclusion and desertification.
2. To specifically assess the effects of immunotherapies and the mechanisms of response to anti-PD1 treatments in the emerging HCC risk factor, NASH.
Descripció
Matèries (anglès)
Citació
Citació
MONTIRONI, Carla. Immunogenomic characterization of HCC and etiology-dependent response to immunotherapies. [consulta: 6 de desembre de 2025]. [Disponible a: https://hdl.handle.net/2445/207980]