A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model
Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS471...
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Frontiers Media S.A.
2022-01-01
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| Series: | Frontiers in Pharmacology |
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| Online Access: | https://www.frontiersin.org/articles/10.3389/fphar.2021.820446/full |
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| author | Yuhua Wei Yufeng Wang Nanbin Liu Ran Qi Yan Xu Kun Li Yu Feng Baomin Shi |
| author_facet | Yuhua Wei Yufeng Wang Nanbin Liu Ran Qi Yan Xu Kun Li Yu Feng Baomin Shi |
| author_sort | Yuhua Wei |
| collection | DOAJ |
| description | Anti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/β-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718. |
| first_indexed | 2024-12-20T19:19:01Z |
| format | Article |
| id | doaj.art-10fc11d067e84a31a542a945409a14d5 |
| institution | Directory Open Access Journal |
| issn | 1663-9812 |
| language | English |
| last_indexed | 2024-12-20T19:19:01Z |
| publishDate | 2022-01-01 |
| publisher | Frontiers Media S.A. |
| record_format | Article |
| series | Frontiers in Pharmacology |
| spelling | doaj.art-10fc11d067e84a31a542a945409a14d52022-12-21T19:29:03ZengFrontiers Media S.A.Frontiers in Pharmacology1663-98122022-01-011210.3389/fphar.2021.820446820446A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse ModelYuhua Wei0Yufeng Wang1Nanbin Liu2Ran Qi3Yan Xu4Kun Li5Yu Feng6Baomin Shi7Department of General Surgery, Tongji Hospital, Tongji University Medical School, Shanghai, ChinaDepartment of General Surgery, Tongji Hospital, Tongji University Medical School, Shanghai, ChinaDepartment of General Surgery, Tongji Hospital, Tongji University Medical School, Shanghai, ChinaDepartment of General Surgery, Tongji Hospital, Tongji University Medical School, Shanghai, ChinaDepartment of General Surgery, Tongji Hospital, Tongji University Medical School, Shanghai, ChinaDepartment of General Surgery, Tongji Hospital, Tongji University Medical School, Shanghai, ChinaShuguang Hospital, Shanghai University of Traditional Chinese Medicine, Shanghai, ChinaDepartment of General Surgery, Tongji Hospital, Tongji University Medical School, Shanghai, ChinaAnti-PD-1/PD-L1 immunotherapy has limited efficacy in hepatocellular carcinoma (HCC) and does not benefit all patients. A FAK inhibitor (VS-4718) has been reported to improve the microenvironment in some tumors. This study aimed to investigate the effect of the combination of the FAK inhibitor VS4718 and anti-PD1 for the treatment of HCC in a mouse model and its possible mechanism of action. The expression of FAK and infiltrated immune cells in human HCC from the data of TCGA were analyzed. A primary murine HCC model was established via protooncogene (c-Met/β-catenin) transfection. The pathological characteristics of tumors were examined after the mice were treated with VS4718 and/or anti-PD1 therapy. This study revealed that FAK is highly expressed in human HCC and is associated with poor prognosis of OS (overall survival) and PFS (progress free survival) in HCC patients. Immune cell infiltration (CD8+ T, Tregs, M0, M2, CAFs and MDSCs) was correlated with FAK expression. In the experimental HCC model, the combination of a FAK inhibitor VS4718 and an anti-PD1 antibody had a better effect than monotherapy against HCC. VS4718 reduced the number of Tregs and macrophages but increased the number of CD8+ T cells in HCC mice. Notably, FAK inhibitor promoted the expression of PD-L1 in HCC. This study suggested that combination of the FAK inhibitor VS4718 and anti-PD1 could be a potential therapy for HCC by improving the immune environment, reducing liver fibrosis and simultaneously preventing PD1 from binding to the increased PD-L1 induced by FAK inhibitor VS4718.https://www.frontiersin.org/articles/10.3389/fphar.2021.820446/fullhepatocellular carcinomaFAK inhibitor (VS4718)PD1PD-L1combination |
| spellingShingle | Yuhua Wei Yufeng Wang Nanbin Liu Ran Qi Yan Xu Kun Li Yu Feng Baomin Shi A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model Frontiers in Pharmacology hepatocellular carcinoma FAK inhibitor (VS4718) PD1 PD-L1 combination |
| title | A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model |
| title_full | A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model |
| title_fullStr | A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model |
| title_full_unstemmed | A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model |
| title_short | A FAK Inhibitor Boosts Anti-PD1 Immunotherapy in a Hepatocellular Carcinoma Mouse Model |
| title_sort | fak inhibitor boosts anti pd1 immunotherapy in a hepatocellular carcinoma mouse model |
| topic | hepatocellular carcinoma FAK inhibitor (VS4718) PD1 PD-L1 combination |
| url | https://www.frontiersin.org/articles/10.3389/fphar.2021.820446/full |
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