Scientific publications

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

Apr 5, 2023 | Magazine: 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


Abstract

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.

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

Our authors

Colaboradora de investigación del Programa de Inmunología e Inmunoterapia del Cima Universidad de Navarra
Dr. Carmen Ochoa Nieto
Sandra Sánchez Gregorio
Saray Garasa Larraza
Irene Olivera Valle
Javier González Vaz
Assunta Cirella
Arantza Azpilicueta Lusarreta
Dr. Álvaro Teijeira Sánchez