Cold‐inducible rna binding protein as a vaccination platform to enhance immunotherapeutic responses against hepatocellular carcinoma

Leyre Silva, Josune Egea, Lorea Villanueva, Marta Ruiz, Diana Llopiz, David Repáraz, Belén Aparicio, Aritz Lasarte‐cia, Juan José Lasarte, Marina Ruiz de Galarreta, Amaia Lujambio, Bruno Sangro, Pablo Sarobe

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17 Scopus citations


Therapies based on immune checkpoint inhibitors (ICPI) have yielded promising albeit limited results in patients with hepatocellular carcinoma (HCC). Vaccines have been proposed as combination partners to enhance response rates to ICPI. Thus, we analyzed the combined effect of a vaccine based on the TLR4 ligand cold‐inducible RNA binding protein (CIRP) plus ICPI. Mice were immunized with vaccines containing ovalbumin linked to CIRP (OVA‐CIRP), with or without ICPI, and antigen‐specific responses and therapeutic efficacy were tested in subcutaneous and orthotopic mouse models of liver cancer. OVA‐CIRP elicited polyepitopic T‐cell responses, which were further enhanced when combined with ICPI (anti‐PD‐1 and anti‐CTLA‐4). Combination of OVA‐CIRP with ICPI enhanced ICPI‐induced therapeutic responses when tested in subcutaneous and intrahepatic B16‐OVA tumors, as well as in the orthotopic PM299L HCC model. This effect was associated with higher OVA‐specific T‐cell responses in the periphery, although many tumor‐infiltrating lymphocytes still displayed an exhausted phenotype. Finally, a new vaccine containing human glypican‐3 linked to CIRP (GPC3‐CIRP) induced clear responses in humanized HLA‐A2.01 transgenic mice, which increased upon combination with ICPI. Therefore, CIRP‐based vaccines may generate anti‐tumor immunity to enhance ICPI efficacy in HCC, although blockade of additional checkpoint molecules and immunosuppressive targets should be also considered.

Original languageEnglish
Article number3397
Pages (from-to)1-18
Number of pages18
Issue number11
StatePublished - Nov 2020


  • Cold‐inducible RNA binding protein
  • Hepatocellular carcinoma
  • Immune checkpoint inhibitors
  • Therapeutic vaccination


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