Abstract
Simple SummaryCurrent immunotherapies based on blockade of immunosuppressive elements provide limited results in liver cancer patients. Here we tested whether combination of this therapy with a vaccine based on the Cold-Inducible RNA Binding Protein (CIRP) would improve its efficacy. Combination of immunotherapy with a CIRP-based vaccine increased vaccine immunogenicity and, when tested in several mouse models of liver cancer, resulted in better therapeutic effects. Despite good immune responses observed in peripheral organs, lymphocytes infiltrating the tumor appeared exhausted, with a weak functional capacity. Finally, by using the same strategy, we prepared a new CIRP-based vaccine containing glypican-3, human antigen commonly found in patients with liver cancer. An equivalent combination enclosing this new vaccine was also highly immunogenic. This suggests that CIRP-based vaccines may enhance the beneficial effects provided by current immunotherapies. However, they should also consider incorporating new elements to overcome limitations observed in tumor lymphocytes.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.
Highlights
Hepatocellular carcinoma (HCC), the dominant form of primary liver cancer, is a leading cause of cancer and of cancer death worldwide [1]
We have recently reported that a trend for higher responses to the PD-1 inhibitor Nivolumab in hepatocellular carcinoma (HCC) patients is associated with the presence of infiltrating T-cells and with inflammatory gene signatures [13]
One week later immune responses in the spleen were measured by IFN-gamma ELISPOT after stimulation with different OVA antigens. (B) OVA-cold-inducible RNA binding protein (CIRP) was used as immunogen alone or in combination with immune checkpoint inhibitors (ICPI) anti-CTLA-4, anti-PD-1, or both antibodies
Summary
Hepatocellular carcinoma (HCC), the dominant form of primary liver cancer, is a leading cause of cancer and of cancer death worldwide [1]. Different etiologies have been described as responsible for generating this tumor (chronic infections caused by hepatitis B and C viruses, alcohol abuse, obesity, etc) all of them have in common the presence of chronic liver inflammation [2]. Despite this role of the inflammatory response in promoting tumor development, the same immune response may exert a beneficial antitumor effect. T-cell infiltration correlates with reduced tumor recurrence following resection and liver transplantation [4,5] These data suggest that strategies promoting the generation/enhancement of antitumor immunity may have a therapeutic effect. Combinations targeting PD-L1 and VEGF [9], CTLA-4 and PD-1 [10] or PD-1 plus the multikinase inhibitor lenvatinib [11] have shown superior response rates
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