C-X-C chemokine receptor 2 (Cxcr2) promotes hepatocellular carcinoma immune evasion via regulating programmed death-ligand 1 (PD-L1)
Abstract Strategies to sensitize hepatocellular carcinomas (HCC) to programmed death-1 (PD1)/programmed death-ligand 1 (PD-L1) inhibitor therapies are important in improving the survival of HCC patients. The aim of the study was to characterize C-X-C chemokine receptor 2 (Cxcr2) as a therapeutic target in HCC and evaluate the effects of Cxcr2 suppression in sensitizing HCC to PD1/PD-L1 inhibitor therapies. To this end, we constructed a Cxcr2-knockout HCC cell line (Hepa1-6 KO) using the CRISPR-Cas9 approach and assessed the tumor growth rate and survival of mice after subcutaneously inoculating Hepa1-6 KO cells in mice. We show that Cxcr2 knockdown does not dramatically inhibit tumor growth and improve mouse survival. In tumor xenografts, the proportion of T cells is not affected but the ratio of M1/M2 macrophage is greatly increased. Cxcr2 knockdown does not alter cell viability but macrophages co-cultured with Hepa1-6 KO cells are shifted to M1 phenotypes compared to WT cells. Hepa-1-6 KO cells exhibit lower levels of PD-L1 expression. c-Myc is suppressed in Hepa1-6 KO cells, which contributes to PD-L1 downregulation. Knockdown of Cxcr2 decreases PD-L1 levels and consequently promotes the shift of macrophages to the M1 phenotype, which is mediated by downregulating c-Myc. In summary, Cxcr2 is a potential target for suppressing immune escape in HCC..
| Medienart: |
Artikel |
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| Erscheinungsjahr: |
2021 |
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| Erschienen: |
2021 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:402 |
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| Enthalten in: |
Biological chemistry - 402(2021), 6 vom: 15. Feb., Seite 729-737 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Wan, Yafeng [VerfasserIn] |
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| Links: |
Volltext [lizenzpflichtig] |
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| Anmerkungen: |
© 2021 Walter de Gruyter GmbH, Berlin/Boston |
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| doi: |
10.1515/hsz-2020-0328 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
OLC2142566073 |
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| 520 | |a Abstract Strategies to sensitize hepatocellular carcinomas (HCC) to programmed death-1 (PD1)/programmed death-ligand 1 (PD-L1) inhibitor therapies are important in improving the survival of HCC patients. The aim of the study was to characterize C-X-C chemokine receptor 2 (Cxcr2) as a therapeutic target in HCC and evaluate the effects of Cxcr2 suppression in sensitizing HCC to PD1/PD-L1 inhibitor therapies. To this end, we constructed a Cxcr2-knockout HCC cell line (Hepa1-6 KO) using the CRISPR-Cas9 approach and assessed the tumor growth rate and survival of mice after subcutaneously inoculating Hepa1-6 KO cells in mice. We show that Cxcr2 knockdown does not dramatically inhibit tumor growth and improve mouse survival. In tumor xenografts, the proportion of T cells is not affected but the ratio of M1/M2 macrophage is greatly increased. Cxcr2 knockdown does not alter cell viability but macrophages co-cultured with Hepa1-6 KO cells are shifted to M1 phenotypes compared to WT cells. Hepa-1-6 KO cells exhibit lower levels of PD-L1 expression. c-Myc is suppressed in Hepa1-6 KO cells, which contributes to PD-L1 downregulation. Knockdown of Cxcr2 decreases PD-L1 levels and consequently promotes the shift of macrophages to the M1 phenotype, which is mediated by downregulating c-Myc. In summary, Cxcr2 is a potential target for suppressing immune escape in HCC. | ||
| 700 | 1 | |a Ge, Ke |4 aut | |
| 700 | 1 | |a Zhou, Weijiang |4 aut | |
| 700 | 1 | |a Lu, Jun |4 aut | |
| 700 | 1 | |a Jia, Changku |4 aut | |
| 700 | 1 | |a Zhu, Hanzhang |0 (orcid)0000-0001-8980-3907 |4 aut | |
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