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

Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular car-cinoma (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 tr...

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Detalles Bibliográficos
Autores: Ochoa-Nieto, M.C. (María del Carmen)|||/items/a26293bb-e79a-42a3-be52-dbf5208f3f89, Sánchez-Gregorio, S. (Sandra)|||/items/0e87cc21-b1fc-49eb-891c-c1a9e6183b5e, Andrea, C.E. (Carlos Eduardo) de|||/items/e487698b-8d56-4c3e-8cba-40e33c78083a, Álvarez-Rodríguez, M. (Maite)|||/items/e298edcf-2e7f-4001-a5e2-244efa1a7781, Olivera-Valle, I. (Irene)|||/items/c3d06db0-d277-4fe8-9b33-59005441fec1, Glez-Vaz, J. (Javier)|||/items/f7aa9f19-9681-425c-8e3d-a6242b8bcbfb, Luri-Rey, C. (Carlos)|||/items/efa6fd23-1164-4af9-8456-9c8fa4fddb8d, Etxeberria, I. (Iñaki)|||/items/73830f45-c05b-49ed-a21a-f7cbacfc8f07, Cirella, A. (Assunta)|||/items/398b3896-8ce3-4831-8ebc-1d86487cd790, Azpilicueta, A. (Arantza)|||/items/9a73625a-e088-4c41-a76f-8fb43aea618e, Berraondo-López, P. (Pedro)|||/items/b1f8ccc3-8e08-4ece-967c-64ccfc0e5b91, Argemí, J. (Josepmaria)|||/items/cc37a6af-13a2-4fe0-846c-4725cca0ae72, Sangro-Gómez-Acebo, B.C. (Bruno Carlos)|||/items/594bbdbb-046a-4ab2-878c-cb4fe577af49, Teijeira-Sánchez, A. (Álvaro)|||/items/8a954ec4-8458-46ea-b8e6-3165119bef30, Melero, I. (Ignacio)|||/items/82113ea8-7ce1-49d5-9ee3-42cf20db1c4e
Tipo de recurso: artículo
Fecha de publicación:2023
País:España
Institución:Universidad de Navarra
Repositorio:Dadun. Depósito Académico Digital de la Universidad de Navarra
Idioma:inglés
OAI Identifier:oai:dadun.unav.edu:10171/67310
Acceso en línea:https://hdl.handle.net/10171/67310
Access Level:acceso abierto
Palabra clave:IL-2
Hepatocellular carcinoma
Immunotherapy
PD-1
CTLA-4
CD137
Descripción
Sumario:Immune checkpoint-inhibitor combinations are the best therapeutic option for advanced hepatocellular car-cinoma (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 addi-tion 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 reg-imens 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.

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