Lu, Xinjun and Deng, Shanshan and Xu, Jiejie and Green, Benjamin L. and Zhang, Honghua and Cui, Guofei and Zhou, Yi and Zhang, Yi and Xu, Hongwei and Zhang, Fapeng and Mao, Rui and Zhong, Sheng and Cramer, Thorsten and Evert, Matthias and Calvisi, Diego F. and He, Yukai and Liu, Chao and Chen, Xintong (2023) Combination of AFP vaccine and immune checkpoint inhibitors slows hepatocellular carcinoma progression in preclinical models. JOURNAL OF CLINICAL INVESTIGATION, 133 (11): e163291. ISSN 0021-9738, 1558-8238
Full text not available from this repository. (Request a copy)Abstract
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, & alpha;-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/& beta;-catenin mouse HCC model. These findings suggest that combining the AFP vaccine and immune checkpoint inhibitors may be effective for AFP (+) HCC treatment.
| Item Type: | Article |
|---|---|
| Uncontrolled Keywords: | RAPAMYCIN COMPLEX 1; T-CELL RESPONSES; ALPHA-FETOPROTEIN; MAMMALIAN TARGET; ASSOCIATION; RECEPTORS; PEPTIDES; TOXICITY; |
| Subjects: | 600 Technology > 610 Medical sciences Medicine |
| Divisions: | Medicine > Lehrstuhl für Pathologie |
| Depositing User: | Dr. Gernot Deinzer |
| Date Deposited: | 09 Apr 2024 06:56 |
| Last Modified: | 09 Apr 2024 06:56 |
| URI: | https://pred.uni-regensburg.de/id/eprint/60727 |
Actions (login required)
 |
View Item |
