Combination of AFP vaccine and immune checkpoint inhibitors slows hepatocellular carcinoma progression in preclinical models

• Published in: The Journal of clinical investigation 2023-06, Vol.133 (11), p.1-13
• Main Authors: Lu, Xinjun, Deng, Shanshan, Xu, Jiejie, Green, Benjamin L, Zhang, Honghua, Cui, Guofei, Zhou, Yi, Zhang, Yi, Xu, Hongwei, Zhang, Fapeng, Mao, Rui, Zhong, Sheng, Cramer, Thorsten, Evert, Matthias, Calvisi, Diego F, He, Yukai, Liu, Chao, Chen, Xin
• Format: Article
• Language: English
• Subjects: Alpha fetoproteins; alpha-Fetoproteins - genetics; alpha-Fetoproteins - metabolism; Analysis; Animal models; Animals; Antigens; Autoantigens; B cells; Biomedical research; c-Myc protein; Cancer vaccines; Cancer Vaccines - therapeutic use; Carcinoma, Hepatocellular - metabolism; Care and treatment; CD8 antigen; CD8-Positive T-Lymphocytes; Cytotoxicity; Drug therapy; Drug therapy, Combination; Health aspects; Hepatocellular carcinoma; Hepatology; Hepatoma; Immune checkpoint inhibitors; Immune Checkpoint Inhibitors - pharmacology; Immune Checkpoint Inhibitors - therapeutic use; Immunization; Immunology; Immunotherapy; Liver cancer; Liver Neoplasms - metabolism; Lymphocytes; Lymphocytes T; Mcl-1 protein; Medical research; Medicine, Experimental; Mice; Myc protein; Myeloid Cell Leukemia Sequence 1 Protein - metabolism; PD-1 protein; PD-L1 protein; Peptides; Physiological aspects; Plasmids; Proteins; T cells; Tumors; Vaccines; α-Fetoprotein
• ISSN: 1558-8238; 0021-9738; 1558-8238
• DOI: 10.1172/JCI163291

Many patients with hepatocellular carcinoma (HCC) do not respond to the first-line immune checkpoint inhibitor treatment. Immunization with effective cancer vaccines is an attractive alternative approach to immunotherapy. However, its efficacy remains insufficiently evaluated in preclinical studies. Here, we investigated HCC-associated self/tumor antigen, α-fetoprotein-based (AFP-based) vaccine immunization for treating AFP (+) HCC mouse models. We found that AFP immunization effectively induced AFP-specific CD8+ T cells in vivo. However, these CD8+ T cells expressed exhaustion markers, including PD1, LAG3, and Tim3. Furthermore, the AFP vaccine effectively prevented c-MYC/Mcl1 HCC initiation when administered before tumor formation, while it was ineffective against full-blown c-MYC/Mcl1 tumors. Similarly, anti-PD1 and anti-PD-L1 monotherapy showed no efficacy in this murine HCC model. In striking contrast, AFP immunization combined with anti-PD-L1 treatment triggered significant inhibition of HCC progression in most liver tumor nodules, while in combination with anti-PD1, it induced slower tumor progression. Mechanistically, we demonstrated that HCC-intrinsic PD-L1 expression was the primary target of anti-PD-L1 in this combination therapy. Notably, the combination therapy had a similar therapeutic effect in the cMet/β-catenin mouse HCC model. These findings suggest that combining the AFP vaccine and immune checkpoint inhibitors may be effective for AFP (+) HCC treatment.