TY - JOUR
T1 - Combination of AFP vaccine and immune checkpoint inhibitors slows hepatocellular carcinoma progression in preclinical models
AU - Lu, Xinjun
AU - Deng, Shanshan
AU - Xu, Jiejie
AU - Green, Benjamin L.
AU - Zhang, Honghua
AU - Cui, Guofei
AU - Zhou, Yi
AU - Zhang, Yi
AU - Xu, Hongwei
AU - Zhang, Fapeng
AU - Mao, Rui
AU - Zhong, Sheng
AU - Cramer, Thorsten
AU - Evert, Matthias
AU - Calvisi, Diego F.
AU - He, Yukai
AU - Liu, Chao
AU - Chen, Xin
N1 - Publisher Copyright:
Copyright: © 2023, Lu et al. This is an open access article published under the terms of the Creative Commons Attribution 4.0 International License.
PY - 2023/6/1
Y1 - 2023/6/1
N2 - 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, antiPD1 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.
AB - 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, antiPD1 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.
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U2 - 10.1172/JCI163291
DO - 10.1172/JCI163291
M3 - Article
C2 - 37040183
AN - SCOPUS:85160966860
SN - 0021-9738
VL - 133
JO - Journal of Clinical Investigation
JF - Journal of Clinical Investigation
IS - 11
M1 - e163291
ER -