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CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment.

ABSTRACT: Clinical sorafenib treatment could activate C-X-C receptor type 4 (CXCR4)/stromal source factor-1α (SDF-1α) axis to aggravate intra-tumoral hypoxia of hepatocellular carcinoma (HCC), which further leads to progression, invasion, metastasis, and immunosuppression of tumors and in return causes resistance to sorafenib therapy. Therefore, a multi-functional oxygen delivery nanoplatform was rationally constructed based on an oxygen-saturated perfluorohexane (PFH)-cored liposome, with the CXCR4 antagonist LFC131 peptides modifying on the surface to simultaneously deliver sorafenib and the CSF1/CSF1R inhibitor PLX3397 (named PFH@LSLP) for sorafenib-resistant HCC treatment. The PFH@LSLP was developed to overcome sorafenib resistance by synergistic effects of the following 3 roles: 1) the O₂-saturated PFH core could alleviate the tumor hypoxia by O₂ supply; 2) the LFC131 peptide recognized the hypoxia-related overexpressed CXCR4 and then blocked SDF-1α/CXCR4 axis to re-sensitize the HCC cells to sorafenib; 3) PLX3397 activated the immune responses via inhibiting the CSF1/CSF1R pathway in TAMs, further enhanced CD8⁺ T cell infiltration to reverse immunosuppression in tumors. Antitumor performance on H22 tumor-bearing mice and HCC patient-derived tumor xenograft (PDX) model showed that PFH@LSLP could overcome sorafenib resistance by synergistic effect of hypoxia attenuation, resistance-related gene regulation, and immune-microenvironment modification.

SUBMITTER: Wang Y

PROVIDER: S-EPMC8965090 | biostudies-literature | 2022 Nov

REPOSITORIES: biostudies-literature

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CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment.

Wang Yuehua Y Wang Zhenjie Z Jia Fei F Xu Qing Q Shu Zhilin Z Deng Junlin J Li Aimin A Yu Meng M Yu Zhiqiang Z

Bioactive materials 20220120

Clinical sorafenib treatment could activate C-X-C receptor type 4 (CXCR4)/stromal source factor-1α (SDF-1α) axis to aggravate intra-tumoral hypoxia of hepatocellular carcinoma (HCC), which further leads to progression, invasion, metastasis, and immunosuppression of tumors and in return causes resistance to sorafenib therapy. Therefore, a multi-functional oxygen delivery nanoplatform was rationally constructed based on an oxygen-saturated perfluorohexane (PFH)-cored liposome, with the CXCR4 antag ...[more]

PMID: 35386453

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Project description:Background: Generally, hepatocellular carcinoma (HCC) exists in an immunosuppressive microenvironment that promotes tumor evasion. Hypoxia can impact intercellular crosstalk in the tumor microenvironment. This study aimed to explore and elucidate the underlying relationship between hypoxia and immunotherapy in patients with HCC. Methods: HCC genomic and clinicopathological datasets were obtained from The Cancer Genome Atlas (TCGA-LIHC), Gene Expression Omnibus databases (GSE14520) and International Cancer Genome Consortium (ICGC-LIRI). The TCGA-LIHC cases were divided into clusters based on single sample gene set enrichment analysis and hierarchical clustering. After identifying patients with immunosuppressive microenvironment with different hypoxic conditions, correlations between immunological characteristics and hypoxia clusters were investigated. Subsequently, a hypoxia-associated score was established by differential expression, univariable Cox regression, and lasso regression analyses. The score was verified by survival and receiver operating characteristic curve analyses. The GSE14520 cohort was used to validate the findings of immune cell infiltration and immune checkpoints expression, while the ICGC-LIRI cohort was employed to verify the hypoxia-associated score. Results: We identified hypoxic patients with immunosuppressive HCC. This cluster exhibited higher immune cell infiltration and immune checkpoint expression in the TCGA cohort, while similar significant differences were observed in the GEO cohort. The hypoxia-associated score was composed of five genes (ephrin A3, dihydropyrimidinase like 4, solute carrier family 2 member 5, stanniocalcin 2, and lysyl oxidase). In both two cohorts, survival analysis revealed significant differences between the high-risk and low-risk groups. In addition, compared to other clinical parameters, the established score had the highest predictive performance at both 3 and 5 years in two cohorts. Conclusion: This study provides further evidence of the link between hypoxic signals in patients and immunosuppression in HCC. Defining hypoxia-associated HCC subtypes may help reveal potential regulatory mechanisms between hypoxia and the immunosuppressive microenvironment, and our hypoxia-associated score could exhibit potential implications for future predictive models.

Project description:UNLABELLED:Sorafenib, a broad tyrosine kinase inhibitor, is the only approved systemic therapy for advanced hepatocellular carcinoma (HCC) but provides limited survival benefits. Recently, immunotherapy has emerged as a promising treatment strategy, but its role remains unclear in HCCs, which are associated with decreased cytotoxic CD8(+) T-lymphocyte infiltration in both murine and human tumors. Moreover, in mouse models after sorafenib treatment intratumoral hypoxia is increased and may fuel evasive resistance. Using orthotopic HCC models, we now show that increased hypoxia after sorafenib treatment promotes immunosuppression, characterized by increased intratumoral expression of the immune checkpoint inhibitor programmed death ligand-1 and accumulation of T-regulatory cells and M2-type macrophages. We also show that the recruitment of immunosuppressive cells is mediated in part by hypoxia-induced up-regulation of stromal cell-derived 1 alpha. Inhibition of the stromal cell-derived 1 alpha receptor (C-X-C receptor type 4 or CXCR4) using AMD3100 prevented the polarization toward an immunosuppressive microenvironment after sorafenib treatment, inhibited tumor growth, reduced lung metastasis, and improved survival. However, the combination of AMD3100 and sorafenib did not significantly change cytotoxic CD8(+) T-lymphocyte infiltration into HCC tumors and did not modify their activation status. In separate experiments, antibody blockade of the programmed death ligand-1 receptor programmed death receptor-1 (PD-1) showed antitumor effects in treatment-naive tumors in orthotopic (grafted and genetically engineered) models of HCC. However, anti-PD-1 antibody treatment had additional antitumor activity only when combined with sorafenib and AMD3100 and not when combined with sorafenib alone. CONCLUSION:Anti-PD-1 treatment can boost antitumor immune responses in HCC models; when used in combination with sorafenib, anti-PD-1 immunotherapy shows efficacy only with concomitant targeting of the hypoxic and immunosuppressive microenvironment with agents such as CXCR4 inhibitors.

Project description:BackgroundCircular RNAs (circRNAs) are a novel type of non-coding RNA, play an important role in the progression of tumors. However, the function and mechanism of circRNAs in regulating immune microenvironment of pancreatic cancer (PC) remain largely unclear.MethodsThe effects of hsa_circ_0046523 expression on proliferation, migration and invasion of PC cells were analyzed by CCK8 and Transwell assays. Flow cytometry was used to detect the proportion of CD4+ T cells, CD8+ T cells and Tregs in peripheral blood mononuclear cells (PBMCs) after co-culture, and the apoptosis, depletion and function of CD8+ T cells. The expression levels of immunoregulatory cytokines were detected by enzyme linked immunosorbent assay (ELISA). The dual-luciferase reporter was performed to determine the interaction between hsa_circ_0046523, miR-148a-3p, and PD-L1. Rescue experiments and PD-L1 blocking experiments were employed to investigate whether hsa_circ_0046523 exerts its biological function by miR-148a-3p/PD-L1 in PC. Furthermore, an immunocompetent murine PC model was established to confirm these findings.ResultsHsa_circ_0046523 expression was remarkably upregulated in PC tissues and cell lines. Moreover, high expression of hsa_circ_0046523 was correlated with advanced pathological stage and poorer prognosis. Hsa_circ_0046523 overexpression promoted the proliferation, migration and invasion of PC cells in vitro. Co-culture experiments confirmed that forced expression of hsa_circ_0046523 could decrease the proportion of CD4+ and CD8+ T cells, as well as increase the proportion of Tregs among peripheral blood mononuclear cells (PBMCs). Meanwhile, hsa_circ_0046523 overexpression promoted the apoptosis and exhaustion of CD8+ T cells, inhibited CD8+ T cell function, increased the secretion of immunosuppressive cytokines IL-10 and TGF-β, and decreased the secretion of immune effector cytokines IFN-γ and IL-2 among PBMCs. Mechanistically, hsa_circ_0046523 exerted its biological function by binding to miR-148a-3p to upregulate PD-L1 expression in PC. Moreover, these immune modulating functions of miR-148a-3p/PD-L1 axis were also confirmed in an immunocompetent murine PC model.ConclusionsOur study suggests that hsa_circ_0046523/miR-148a-3p/PD-L1 regulatory axis mediates PC immunosuppressive microenvironment and these molecules are expected to be new targets for remodeling tumor immune microenvironment of PC.

Dataset Information

CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment.

Publications

CXCR4-guided liposomes regulating hypoxic and immunosuppressive microenvironment for sorafenib-resistant tumor treatment.

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