Neoantigen vaccination augments antitumor effects of anti-PD-1 on mouse hepatocellular carcinoma

Immune checkpoint inhibitors are groundbreaking resources for cancer therapy. However, only a few patients with hepatocellular carcinoma (HCC) have shown positive responses to anti-PD-1 therapy. Neoantigens are sequence-altered proteins resulting from somatic mutations in cancer. This study identifi...

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Veröffentlicht in:Cancer letters 2023-06, Vol.563, p.216192-216192, Article 216192
Hauptverfasser: Yang, Shih-Feng, Weng, Meng-Tzu, Liang, Ja-Der, Chiou, Ling-Ling, Hsu, Yu-Chen, Lee, Ying-Te, Liu, Shin-Yun, Wu, Meng-Chuan, Chou, Huei-Chi, Wang, Li-Fang, Yu, Shu-Han, Lee, Hsuan-Shu, Sheu, Jin-Chuan
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Sprache:eng
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Zusammenfassung:Immune checkpoint inhibitors are groundbreaking resources for cancer therapy. However, only a few patients with hepatocellular carcinoma (HCC) have shown positive responses to anti-PD-1 therapy. Neoantigens are sequence-altered proteins resulting from somatic mutations in cancer. This study identified the neoantigens of Hep-55.1C and Dt81 Hepa1-6 HCCs by comparing their whole exome sequences with those of a normal C57BL/6 mouse liver. Immunogenic long peptides were pooled as peptide vaccines. The vaccination elicited tumor-reactive immune responses in C57BL/6 mice, as demonstrated by IFN-γ ELISPOT and an in vitro killing assay of splenocytes. In the treatment of three mouse HCC models, combined neoantigen vaccination and anti-PD-1 resulted in more significant tumor regression than monotherapies. Flow cytometry of the tumor-infiltrating lymphocytes showed decreased Treg cells and monocytic myeloid-derived suppressor cells, increased CD8+ T cells, enhanced granzyme B expression, and reduced exhaustion-related markers PD-1 and Lag-3 on CD8+ T cells in the combination group. These findings provide a strong rationale for conducting clinical studies of using neoantigen vaccination in combination with anti-PD-1 to treat patients with HCC. •Neoantigen vaccination can notably enhance the antitumor effects of anti-PD-1 on mouse HCC.•Combination of neoantigen vaccination and anti-PD-1 elicits the most potent antitumor response and leads to better survival.•Combination treatment dramatically reshaped the tumor microenvironment than anti-PD-1 monotherapy group.•The results indicate that this combination therapy can be applied to treat patients with hepatocellular carcinoma.
ISSN:0304-3835
1872-7980
DOI:10.1016/j.canlet.2023.216192