Nanodrug modified with engineered cell membrane targets CDKs to activate aPD-L1 immunotherapy against liver metastasis of immune-desert colon cancer
Copyright © 2024 Elsevier B.V. All rights reserved..
Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy.
| Medienart: |
E-Artikel |
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| Erscheinungsjahr: |
2024 |
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| Erschienen: |
2024 |
| Enthalten in: |
Zur Gesamtaufnahme - volume:369 |
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| Enthalten in: |
Journal of controlled release : official journal of the Controlled Release Society - 369(2024) vom: 02. Apr., Seite 309-324 |
| Sprache: |
Englisch |
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| Beteiligte Personen: |
Ding, Dongbing [VerfasserIn] |
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| Links: |
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| Themen: |
CDKs |
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| Anmerkungen: |
Date Revised 04.04.2024 published: Print-Electronic Citation Status Publisher |
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| doi: |
10.1016/j.jconrel.2024.03.052 |
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| funding: |
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| Förderinstitution / Projekttitel: |
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| PPN (Katalog-ID): |
NLM37044292X |
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| 520 | |a Immunotherapy based on the PD-1/PD-L1 axis blockade has no benefit for patients diagnosed with colon cancer liver metastasis (CCLM) for the microsatellite stable/proficient mismatch repair (MSS/pMMR)) subtype, which is known as an immune-desert cancer featuring poor immunogenicity and insufficient CD8+ T cell infiltration in the tumor microenvironment. Here, a multifunctional nanodrug carrying a cyclin-dependent kinase (CDK)1/2/5/9 inhibitor and PD-L1 antibody is prepared to boost the immune checkpoint blockade (ICB)-based immunotherapy against MSS/pMMR CCLM via reversing the immunosuppressive tumor microenvironment. To enhance the MSS/pMMR CCLM-targeting efficacy, we modify the nanodrug with PD-L1 knockout cell membrane of this colon cancer subtype. First, CDKs inhibitor delivered by nanodrug down-regulates phosphorylated retinoblastoma and phosphorylated RNA polymerase II and meanwhile arrests the G2/M cell cycle in CCLM to promote immunogenic signal release, stimulate dendritic cell maturation, and enhance CD8+ T cell infiltration. Moreover, CDKi suppresses the secretion of immunosuppressive cytokines in tumor-associated myeloid cells sensitizing ICB therapy in CCLM. Notably, the great efficacy to activate immune responses is demonstrated in the patient-derived xenograft model and the patient-derived organoid model as well, revealing a clinical application potential. Overall, our study represents a promising therapeutic approach for targeting liver metastasis, remolding the tumor immune microenvironment (TIME), and enhancing the response of MSS/pMMR CCLM to boost ICB immunotherapy | ||
| 650 | 4 | |a Journal Article | |
| 650 | 4 | |a CDKs | |
| 650 | 4 | |a Engineered cell membrane | |
| 650 | 4 | |a Immunotherapy | |
| 650 | 4 | |a Microsatellite stable | |
| 650 | 4 | |a Nanodrug | |
| 650 | 4 | |a colon cancer liver metastasis | |
| 700 | 1 | |a Liang, Rongpu |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Tan |e verfasserin |4 aut | |
| 700 | 1 | |a Lan, Tianyun |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Yiquan |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Shengxin |e verfasserin |4 aut | |
| 700 | 1 | |a He, Guanhui |e verfasserin |4 aut | |
| 700 | 1 | |a Ren, Jiannan |e verfasserin |4 aut | |
| 700 | 1 | |a Li, Weibo |e verfasserin |4 aut | |
| 700 | 1 | |a Zheng, Zongheng |e verfasserin |4 aut | |
| 700 | 1 | |a Chen, Tufeng |e verfasserin |4 aut | |
| 700 | 1 | |a Fang, Jiafeng |e verfasserin |4 aut | |
| 700 | 1 | |a Huang, Lijun |e verfasserin |4 aut | |
| 700 | 1 | |a Shuai, Xintao |e verfasserin |4 aut | |
| 700 | 1 | |a Wei, Bo |e verfasserin |4 aut | |
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