Risultati per: Linee guida per la gestione del carcinoma epatocellulare negli adulti

This nonrandomized clinical trial evaluates the efficacy and safety of a tailored approach with nivolumab plus ipilimumab as an immunotherapeutic boost in patients with metastatic urothelial carcinoma.

La malattia trasmessa dalle zanzare comincia a diffondersi anche a queste latitudini a causa dei cambiamenti climatici

The advent of immune checkpoint inhibitors, particularly monoclonal antibodies (mAbs) that target the programmed cell death protein 1 (PD-1) or its ligand (PD-L1), has revolutionised cancer treatment across various malignancies. Despite this groundbreaking progress, a considerable cohort of patients fails to derive benefit from anti-PD(L)1 mAb therapy due to primary and secondary resistance mechanisms. The percentage of patients who respond to these treatments varies among different tumour types, ranging from 40% in more sensitive tumours, like metastatic melanoma, to virtually zero in less sensitive tumours such as glioblastoma.1 Hepatocellular carcinoma (HCC), one of the deadliest solid tumours, emerges as a moderately sensitive tumour, where monotherapy with anti-PD(L)1 agents demonstrates a response in only about 15% of cases.2 These encouraging yet constrained clinical outcomes have elevated immunotherapy to a pivotal status in clinical practice, instigating evaluations of combinatory approaches with other agents alongside anti-PD(L)1 mAbs to…

Objective
The gain of function (GOF) CTNNB1 mutations (CTNNB1 GOF ) in hepatocellular carcinoma (HCC) cause significant immune escape and resistance to anti-PD-1. Here, we aimed to investigate the mechanism of CTNNB1 GOF HCC-mediated immune escape and raise a new therapeutic strategy to enhance anti-PD-1 efficacy in HCC.

Design
RNA sequencing was performed to identify the key downstream genes of CTNNB1 GOF associated with immune escape. An in vitro coculture system, murine subcutaneous or orthotopic models, spontaneously tumourigenic models in conditional gene-knock-out mice and flow cytometry were used to explore the biological function of matrix metallopeptidase 9 (MMP9) in tumour progression and immune escape. Single-cell RNA sequencing and proteomics were used to gain insight into the underlying mechanisms of MMP9.

Results
MMP9 was significantly upregulated in CTNNB1 GOF HCC. MMP9 suppressed infiltration and cytotoxicity of CD8+ T cells, which was critical for CTNNB1 GOF to drive the suppressive tumour immune microenvironment (TIME) and anti-PD-1 resistance. Mechanistically, CTNNB1 GOF downregulated sirtuin 2 (SIRT2), resulting in promotion of β-catenin/lysine demethylase 4D (KDM4D) complex formation that fostered the transcriptional activation of MMP9. The secretion of MMP9 from HCC mediated slingshot protein phosphatase 1 (SSH1) shedding from CD8+ T cells, leading to the inhibition of C-X-C motif chemokine receptor 3 (CXCR3)-mediated intracellular of G protein-coupled receptors signalling. Additionally, MMP9 blockade remodelled the TIME and potentiated the sensitivity of anti-PD-1 therapy in HCC.

Conclusions
CTNNB1 GOF induces a suppressive TIME by activating secretion of MMP9. Targeting MMP9 reshapes TIME and potentiates anti-PD-1 efficacy in CTNNB1 GOF HCC.