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 - Funding Information:
Conflicts of Interest: B. Sangro reports consultancy fees from Adaptimmune, Astra Zeneca, Bayer, BMS, BTG, Eli Lilly, Ipsen, Novartis, Merck, Roche, Sirtex Medical, Terumo; and research grants from BMS and Sirtex Medical. The other authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript, or in the decision to publish the results.
Funding Information:
Funding: This research was funded by grants from Caixaimpulse Program (CI17‐00064), Instituto de Salud Carlos III co‐financed by European FEDER funds (PI17/00249), Fundación Bancaria La Caixa “Hepacare” project, Gobierno de Navarra “AGATA” project and “Murchante contra el Cáncer” initiative to P. Sarobe. J.J.Lasarte is funded by Ministerio de Ciencia e Innovación (PID2019‐108989RB‐I00). B. Sangro is funded by Instituto de Salud Carlos III /EU TRANSCAN‐2 (AC16/00065) and Instituto de Salud Carlos III co‐financed by European FEDER funds (PI19/00742). M. Ruiz de Galarreta was supported by the Fundación Alfonso Martín Escudero Fellowship and the Damon Runyon‐Rachleff Innovation Award (DR52‐18). A. Lujambio was supported by a Damon Runyon‐Rachleff Innovation Award (DR52‐18), R37 Merit Award (R37CA230636), DoD Career Development Award (CA150178), DoD Translational Team Science Award (CA150272P2), and the Icahn School of Medicine at Mount Sinai.
Funding Information:
This research was funded by grants from Caixaimpulse Program (CI17?00064), Instituto de Salud Carlos III co?financed by European FEDER funds (PI17/00249), Fundaci?n Bancaria La Caixa ?Hepacare? project, Gobierno de Navarra ?AGATA? project and ?Murchante contra el C?ncer? initiative to P. Sarobe. J.J.Lasarte is funded by Ministerio de Ciencia e Innovaci?n (PID2019?108989RB?I00). B. Sangro is funded by Instituto de Salud Carlos III /EU TRANSCAN?2 (AC16/00065) and Instituto de Salud Carlos III co?financed by European FEDER funds (PI19/00742). M. Ruiz de Galarreta was supported by the Fundaci?n Alfonso Mart?n Escudero Fellowship and the Damon Runyon?Rachleff Innovation Award (DR52?18). A. Lujambio was supported by a Damon Runyon?Rachleff Innovation Award (DR52?18), R37 Merit Award (R37CA230636), DoD Career Development Award (CA150178), DoD Translational Team Science Award (CA150272P2), and the Icahn School of Medicine at Mount Sinai. Acknowledgments: We thank Kroemer and Alemany for their kind gift of tumor cell lines, and S. Hervas?Stubbs and U. Manche?o for their help with hepatic tumor models.
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 -