Combination of AFP vaccine and immune checkpoint inhibitors slows hepatocellular carcinoma progression in preclinical models
Xinjun Lu, Shanshan Deng, Jiejie Xu, Benjamin L. Green, Honghua Zhang, Guofei Cui, Yi Zhou, Yi Zhang, Hongwei Xu, Fapeng Zhang, Rui Mao, Sheng Zhong, Thorsten Cramer, Matthias Evert, Diego F. Calvisi, Yukai He, Chao Liu, Xin Chen
Xinjun Lu, Shanshan Deng, Jiejie Xu, Benjamin L. Green, Honghua Zhang, Guofei Cui, Yi Zhou, Yi Zhang, Hongwei Xu, Fapeng Zhang, Rui Mao, Sheng Zhong, Thorsten Cramer, Matthias Evert, Diego F. Calvisi, Yukai He, Chao Liu, Xin Chen
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Research Article Hepatology Immunology

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

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, 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.

Authors

Xinjun Lu, Shanshan Deng, Jiejie Xu, Benjamin L. Green, Honghua Zhang, Guofei Cui, Yi Zhou, Yi Zhang, Hongwei Xu, Fapeng Zhang, Rui Mao, Sheng Zhong, Thorsten Cramer, Matthias Evert, Diego F. Calvisi, Yukai He, Chao Liu, Xin Chen

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Figure 7

Deletion of PD-L1 does not affect tumor growth.

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Deletion of PD-L1 does not affect tumor growth. (A) Study design. (B) Su...
(A) Study design. (B) Survival curve of c-MYC/Mcl1/sgPD-L1 with or without AFP immunization. Kaplan-Meier test was used for survival analysis. (C) Pictures of representative livers from B, the numbers indicate the liver weight and weeks from hydrodynamic injection to sacrifice date for that particular mouse. (D and E) Western blot (D) and TA cloning sequencing results (E) from the c-MYC/Mcl1/sgPD-L1 tumors also confirm the deletion of PD-L1 in the tumors. The TA cloning sequencing reads are aligned with mouse GRCm38/mm10 genome at the UCSC genome browser (https://genome.ucsc.edu/). PD-L1 is also called CD274, and the gRNAs are designed to target the third exon of Pd-l1. c-MYC/Mcl1/sgPD-L1 no. 1 and c-MYC/Mcl1/sgPD-L1 no. 2 indicate the depletion of the whole sequence between the 2 sgPD-L1 gRNAs, c-MYC/Mcl1/sgPD-L1 no. 3 indicate the reversion sequence between the 2 sgPD-L1 gRNAs. All these sequence edits cause PD-L1 gene sequence frame-shift and early stop. wpi, weeks after injection; Immu, immunization.