Publicaciones científicas

Synergistic effects of combined immunotherapy strategies in a model of multifocal hepatocellular carcinoma

05-abr-2023 | Revista: Cell Reports. Medicine

Maria Carmen Ochoa  1 , Sandra Sanchez-Gregorio  2 , Carlos E de Andrea  3 , Saray Garasa  4 , Maite Alvarez  4 , Irene Olivera  4 , Javier Glez-Vaz  4 , Carlos Luri-Rey  4 , Iñaki Etxeberria  5 , Assunta Cirella  5 , Arantza Azpilikueta  4 , Pedro Berraondo  6 , Josepmaria Argemi  7 , Bruno Sangro  7 , Alvaro Teijeira  1 , Ignacio Melero  8


Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular carcinoma (HCC) patients, but improvements in efficacy are needed to improve response rates.

We develop a multifocal HCC model to test immunotherapies by introducing c-myc using hydrodynamic gene transfer along with CRISPR-Cas9-mediated disruption of p53 in mouse hepatocytes. Additionally, induced co-expression of luciferase, EGFP, and the melanosomal antigen gp100 facilitates studies on the underlying immunological mechanisms.

We show that treatment of the mice with a combination of anti-CTLA-4 + anti-PD1 mAbs results in partial clearance of the tumor with an improvement in survival. However, the addition of either recombinant IL-2 or an anti-CD137 mAb markedly improves both outcomes in these mice.

Combining tumor-specific adoptive T cell therapy to the aCTLA-4/aPD1/rIL2 or aCTLA-4/aPD1/aCD137 regimens enhances efficacy in a synergistic manner. As shown by multiplex tissue immunofluorescence and intravital microscopy, combined immunotherapy treatments enhance T cell infiltration and the intratumoral performance of T lymphocytes.

CITA DEL ARTÍCULO  Cell Rep Med. 2023 Apr 5;101009.  doi: 10.1016/j.xcrm.2023.101009