Dendritic cell subsets in cancer immunity and tumor antigen sensing

Prete, Annalisa Del; Salvi, Valentina; Soriani, Alessandra; Laffranchi, Mattia; Sozio, Francesca; Bosisio, Daniela; Sozzani, Silvano

doi:10.1038/s41423-023-00990-6

Cited by 174 publications

(68 citation statements)

References 257 publications

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“…Consistent with previous data, the free-form STING agonist did not induce any appreciable change. The increased maturation marker expression could be due to a combination of type I IFN production due to STING activation and exposure to tumor antigen. , The indispensable role of secondary lymphoid organ (SLO)-resident CD8 + DCs in priming cytotoxic T-lymphocytes (CTLs) and subsequent cellular responses to both tumors and pathogens is well-established; thus, their expansion brought about by polySTING indicates stronger CD8 + T cell priming. The increase in CD103 + DCs in the TDLN of polySTING-treated animals compared to control animals is in line with a report showing CD103 + DCs passing tumor antigen to CTL-priming CD8 + DCs via synaptic transfer after migration to TDLNs .…”

Section: Resultsmentioning

confidence: 99%

Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy

Nguyen,

Song,

Jokonya

et al. 2024

ACS Cent. Sci.

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The Stimulator of Interferon Genes (STING) pathway is a promising target for cancer immunotherapy. Despite recent advances, therapies targeting the STING pathway are often limited by routes of administration, suboptimal STING activation, or off-target toxicity. Here, we report a dendritic cell (DC)-targeted polymeric prodrug platform (polySTING) that is designed to optimize intracellular delivery of a diamidobenzimidazole (diABZI) smallmolecule STING agonist while minimizing off-target toxicity after parenteral administration. PolySTING incorporates mannose targeting ligands as a comonomer, which facilitates its uptake in CD206 + / mannose receptor + professional antigen-presenting cells (APCs) in the tumor microenvironment (TME). The STING agonist is conjugated through a cathepsin B-cleavable valine-alanine (VA) linker for selective intracellular drug release after receptor-mediated endocytosis. When administered intravenously in tumor-bearing mice, polySTING selectively targeted CD206 + /mannose receptor + APCs in the TME, resulting in increased cross-presenting CD8 + DCs, infiltrating CD8 + T cells in the TME as well as maturation across multiple DC subtypes in the tumor-draining lymph node (TDLN). Systemic administration of polySTING slowed tumor growth in a B16-F10 murine melanoma model as well as a 4T1 murine breast cancer model with an acceptable safety profile. Thus, we demonstrate that polySTING delivers STING agonists to professional APCs after systemic administration, generating efficacious DC-driven antitumor immunity with minimal side effects. This new polymeric prodrug platform may offer new opportunities for combining efficient targeted STING agonist delivery with other selective tumor therapeutic strategies.

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Section: Resultsmentioning

confidence: 99%

Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy

Nguyen,

Song,

Jokonya

et al. 2024

ACS Cent. Sci.

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“…It was all known that DC played an essential role in the antitumor immune responses triggered by radiotherapy. [ 17 ] To evaluate the combination efficacy of Tpp‐Met@MnO 2 @Alb and radiotherapy in inducing ICD, the typical immunogenic substances high‐mobility group box 1 (HMGB1) was measured via immunofluorescence assay (Figure S16, Supporting Information). As indicated, radiotherapy caused an obvious increase in the release of HMGB1, which was further raised when Tpp‐Met@MnO 2 @Alb was treated in combination with radiotherapy (Figure S16, Supporting Information).…”

Section: Resultsmentioning

confidence: 99%

A Hybrid Nanoadjuvant Simultaneously Depresses PD‐L1/TGF‐β1 and Activates cGAS‐STING Pathway to Overcome Radio‐Immunotherapy Resistance

Yi,

Jiang,

Zhou

et al. 2024

Advanced Materials

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Currently, certain cancer patients exhibit resistance to radiotherapy due to reduced DNA damage under hypoxic conditions and acquired immune tolerance triggered by transforming growth factor‐β1 (TGF‐β1) and membrane‐localized programmed death ligand‐1 (PD‐L1). Meanwhile, cytoplasm‐distributed PD‐L1 induces radiotherapy resistance through accelerating DNA damage repair (DDR). However, the disability of clinically used PD‐L1 antibodies in inhibiting cytoplasm‐distributed PD‐L1 limited their effectiveness. Therefore, we developed a nanoadjuvant to sensitize cancer to radiotherapy via multi‐level immunity activation through depressing PD‐L1 and TGF‐β1 by Triphenylphosphine‐derived Metformin (Tpp‐Met), and activating the cGAS‐STING pathway by generating Mn2+ from MnO2 and producing more dsDNA via reversing tumor hypoxia and impairing DDR. Thus, Tpp‐Met@MnO2@Alb effectively enhanced the efficiency of radiotherapy to inhibit the progression of irradiated local and abscopal tumors and tumor lung metastases, offering a long‐term memory of antitumor immunity without discernible side effects. Overall, Tpp‐Met@MnO2@Alb had the potential to be clinically applied for overcoming radio‐immunotherapy resistance.This article is protected by copyright. All rights reserved

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“…5D ). MHCII molecules are critical for presenting antigens to CD4+ T cells, and an upregulation suggests an enhanced capacity for the presentation of exogenously derived tumor-specific peptide antigens, potentially leading to a more robust anti-tumor immune response 38 . Additionally, iEF treatment increased the enrichment of Type 1 DCs (DC1s) compared to the control group ( Fig.…”

Section: Resultsmentioning

confidence: 99%

Induced electric fields inhibit breast cancer growth and metastasis by modulating the immune tumor microenvironment

Charan,

Jones,

Ahirwar

et al. 2024

Preprint

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Despite tremendous advances in oncology, metastatic triple-negative breast cancer remains difficult to treat and manage with established therapies. Here, we show in mice with orthotopic triple-negative breast tumors that alternating (100 kHz), and low intensity (<1 mV/cm) induced electric fields (iEFs) significantly reduced primary tumor growth and distant lung metastases. Non-contact iEF treatment can be delivered safely and non-invasively in vivo via a hollow, rectangular solenoid coil. We discovered that iEF treatment enhances anti-tumor immune responses at both the primary breast and secondary lung sites. In addition, iEF reduces immunosuppressive TME by reducing effector CD8+ T cell exhaustion and the infiltration of immunosuppressive immune cells. Furthermore, iEF treatment reduced lung metastasis by increasing CD8+ T cells and reducing immunosuppressive Gr1+ neutrophils in the lung microenvironment. We also observed that iEFs reduced the metastatic potential of cancer cells by inhibiting epithelial-to-mesenchymal transition. By introducing a non-invasive and non-toxic electrotherapeutic for inhibiting metastatic outgrowth and enhancing anti-tumor immune response in vivo, treatment with iEF technology could add to a paradigm-shifting strategy for cancer therapy.

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Dendritic cell subsets in cancer immunity and tumor antigen sensing

Cited by 174 publications

References 257 publications

Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy

Mannosylated STING Agonist Drugamers for Dendritic Cell-Mediated Cancer Immunotherapy

A Hybrid Nanoadjuvant Simultaneously Depresses PD‐L1/TGF‐β1 and Activates cGAS‐STING Pathway to Overcome Radio‐Immunotherapy Resistance

Induced electric fields inhibit breast cancer growth and metastasis by modulating the immune tumor microenvironment

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