Dataset Information

Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8⁺ T Cells.

ABSTRACT: Intratumoral CD8⁺ T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T-cell-mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects of these old drugs has not been realized. The self-degradable PMI nanogels carrying two repurposed immune modulators, imiquimod (Imi) and metformin (Met), are reported for TME-responsive drug release. It remodels the TME through the following aspects: 1) promoting dendritic cells maturation, 2) repolarizing M2-like tumor-associated macrophages, and 3) downregulating PD-L1 expression. Ultimately, PMI nanogels reshaped the immunosuppressive TME and efficiently promote CD8⁺ T cell infiltration and activation. These results support that PMI nanogels can potentially be an effective combination drug for enhancing the antitumor immune response of anti-PD-1 antibodies.

SUBMITTER: Tian H

PROVIDER: S-EPMC10375179 | biostudies-literature | 2023 Jul

REPOSITORIES: biostudies-literature

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Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8<sup>+</sup> T Cells.

Tian Hao H Li Wenxi W Wang Guohao G Tian Ye Y Yan Jie J Zhou Songtao S Yu Xinying X Li Bei B Dai Yunlu Y

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 20230505 21

Intratumoral CD8<sup>+</sup> T cells are crucial for effective cancer immunotherapy, but an immunosuppressive tumor microenvironment (TME) contributes to dysfunction and insufficient infiltration. Drug repurposing has successfully led to new discoveries among existing clinical drugs for use as immune modulators to ameliorate immunosuppression in TME and reactivate T-cell-mediated antitumor immunity. However, due to suboptimal tumor bioavailability, the full potential of immunomodulatory effects ...[more]

PMID: 37144520

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Project description:Liver fibrosis is a hard-to-treat disease with liver transplantation as only effective curation to this date. During disease progression, immune suppressive macrophages dominate and support fibrosis formation by replacement of functional parenchyma with collagen-dominating scare tissue. To alter the macrophage behavior, a pH-degradable, nanogel-based delivery system was developed for the covalent conjugation of the clinically approved bisphosphonate alendronate. The nanocarrier mediates the drugs’ delivery into hepatic nonparenchymal cells after intravenous administration and, thereby, triggers a macrophage repolarization against fibrosis progression. This approach may provide a significant contribution to establish further nanotherapeutic delivery strategies to effectively treat liver fibrosis. Immune suppressive macrophages contribute to the progression of several diseases including cancer and fibrosis. Especially in chronically damaged liver tissues they trigger the replacement of functional parenchyma by collagen-dominating scare tissue. In this study, we aimed to intervene into this cascade by repolarizing the macrophage phenotype via a pH-degradable, squaric ester-based nanogel carrier system. This nanotechnology platform enables a selective covalent conjugation of the highly water-soluble bisphosphonate alendronate and, thus, its safe and efficient delivery to hepatic nonparenchymal cells of fibrotic livers after intravenous administration. The bisphosphonate triggers a reprogramming of profibrotic M2- towards antifibrotic M1-phenotype macrophages affording an fibrolytic outcome, as verified both on mRNA and protein level. Further insights by genomic and proteomic studies confirm the macrophages’ repolarization and thus corroborate the virtue of the nanogels as biocompatible nanocarrier platform for hepatotropic bisphosphonate delivery. Beyond preventing liver fibrosis progression, these nanogels may therefore represent an attractive device for further nanotherapeutic interventions in M2-type macrophage dominating diseases.

Project description:BackgroundThe MTA1 protein encoded by metastasis-associated protein 1 (MTA1) is a key component of the ATP-dependent nucleosome remodeling and deacetylase (NuRD) complex, which is widely upregulated in cancers. MTA1 extensively affects downstream gene expression by participating in chromatin remodeling. Although it was defined as a metastasis-associated gene in first reports and metastasis is a process prominently affected by the tumor microenvironment, whether it affects the microenvironment has not been investigated. In our study, we elucidated the regulatory effect of MTA1 on tumor-associated macrophages (TAMs) and how this regulation affects the antitumor effect of cytotoxic T lymphocytes (CTLs) in the tumor microenvironment of colorectal cancer.MethodsWe detected the cytokines affected by MTA1 expression via a cytokine antibody array in control HCT116 cells and HCT116 cells overexpressing MTA1. Multiplex IHC staining was conducted on a colorectal cancer tissue array from our cancer cohort. Flow cytometry (FCM) was performed to explore the polarization of macrophages in the coculture system and the antitumor killing effect of CTLs in the coculture system. Bioinformatics analysis was conducted to analyze the Cancer Genome Atlas (TCGA) colorectal cancer cohort and single-cell RNA-seq data to assess the immune infiltration status of the TCGA colorectal cancer cohort and the functions of myeloid cells.ResultsMTA1 upregulation in colorectal cancer was found to drive an immunosuppressive tumor microenvironment. In the tumor microenvironment of MTA1-upregulated colorectal cancer, although CD8+ T cells were significantly enriched, macrophages were significantly decreased, which impaired the CTL effect of the CD8+ T cells on tumor cells. Moreover, upregulated MTA1 in tumor cells significantly induced infiltrated macrophages into tumor-associated macrophage phenotypes and further weakened the cytotoxic effect of CD8+ T cells.ConclusionUpregulation of MTA1 in colorectal cancer drives an immunosuppressive tumor microenvironment by decreasing the microphages from the tumor and inducing the residual macrophages into tumor-associated microphage phenotypes to block the activation of the killing CTL, which contributes to cancer progression.

Project description:PurposeImmune checkpoint inhibitors have recently been approved by the US FDA as first and/or second line therapy in a subset of cancer types. Recent evidence suggests that the quantity of tumor infiltrating lymphocytes (TILs) influences the likelihood of response to immune checkpoint inhibitors. Here, we set out to assess the density of CD8+ lymphocytes in a wide range of different cancer types and subtypes.MethodsThe density of CD8+ lymphocytes was compared across different cancer types using tissue microarrays (TMAs) composed of up to 50 tumor samples each from 84 different cancer types and subtypes. In total 2652 cancers and 608 normal tissues were successfully analyzed by CD8 immunohistochemistry followed by automated image analysis of digitized slides.ResultsWe found that the median CD8+ lymphocyte counts ranged from 6 cells/mm2 in pleomorphic adenoma up to 1573 cells/mm2 in Hodgkin's lymphoma. The CD8 counts were generally lower in normal tissues compared to cancer tissues. Blood vessels of the spleen were the only non-lymphatic tissue staining positive for CD8. Tumor types approved for checkpoint inhibitor therapy, including malignant melanoma (81), muscle invasive urothelial carcinoma (119), small cell lung cancer (120), clear cell renal cell cancer (153), squamous cell carcinoma (189) and adenocarcinoma of the lung (328) as well as Hodgkin's lymphoma (1573) were all ranking among the upper half of our list. Comparably high CD8 densities (median cells/mm2) were also found in several rare and aggressive cancer types including Merkel cell carcinoma (70), angiosarcoma (95), anaplastic thyroid cancer (156) and embryonal carcinoma of the testis (186). In 73 of the 84 analyzed cancer types, the highly variable CD8 counts occasionally exceeded the average CD8 count of tumors for which checkpoint inhibitors have been approved.ConclusionThese data support the concept that among most tumor types at least some individual cancers may benefit from treatment with immune checkpoint inhibitors.

Dataset Information

Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8⁺ T Cells.

Publications

Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8<sup>+</sup> T Cells.

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Dataset Information

Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8+ T Cells.

Publications

Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8<sup>+</sup> T Cells.

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets

Self-Degradable Nanogels Reshape Immunosuppressive Tumor Microenvironment via Drug Repurposing Strategy to Reactivate Cytotoxic CD8⁺ T Cells.