TY - JOUR
T1 - Cold‐inducible rna binding protein as a vaccination platform to enhance immunotherapeutic responses against hepatocellular carcinoma
AU - Silva, Leyre
AU - Egea, Josune
AU - Villanueva, Lorea
AU - Ruiz, Marta
AU - Llopiz, Diana
AU - Repáraz, David
AU - Aparicio, Belén
AU - Lasarte‐cia, Aritz
AU - Lasarte, Juan José
AU - de Galarreta, Marina Ruiz
AU - Lujambio, Amaia
AU - Sangro, Bruno
AU - Sarobe, Pablo
N1 - Publisher Copyright:
© 2020 by the authors. Licensee MDPI, Basel, Switzerland.
PY - 2020/11
Y1 - 2020/11
N2 - 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.
AB - 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.
KW - Cold‐inducible RNA binding protein
KW - Hepatocellular carcinoma
KW - Immune checkpoint inhibitors
KW - Therapeutic vaccination
UR - http://www.scopus.com/inward/record.url?scp=85096134329&partnerID=8YFLogxK
U2 - 10.3390/cancers12113397
DO - 10.3390/cancers12113397
M3 - Article
AN - SCOPUS:85096134329
SN - 2072-6694
VL - 12
SP - 1
EP - 18
JO - Cancers
JF - Cancers
IS - 11
M1 - 3397
ER -