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Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway.

ABSTRACT: Immunogenic Cell Death (ICD) represents a mechanism of enhancing T cell-driven response against tumor cells. The process is enabled by release of damage-associated molecular patterns (DAMPs) and cytokines by dying cells. Based on molecular studies and clinical marker assessment, ICD can be a new target for cancer chemotherapy hitherto restricted to a few conventional anticancer drugs. In view of the development of small molecules in targeted cancer therapy, we reported the preliminary evidence on the role of the natural product lepadin A (1) as a novel ICD inducer. Here we describe the ICD mechanism of lepadin A (1) by proving the translocation of the protein calreticulin (CRT) to the plasma membrane of human A2058 melanoma cells. CRT exposure is an ICD marker in clinical studies and was associated with the activation of the intrinsic apoptotic pathway in A2058 cells with lepadin A (1). After the treatment, the tumour cells acquired the ability to activate dendritic cells (DCs) with cytokine release and costimulatory molecule expression that is consistent with a phenotypic profile committed to priming T lymphocytes via a CD91-dependent mechanism. The effect of lepadin A (1) was dose-dependent and comparable to the response of the chemotherapy drug doxorubicin (2), a well-established ICD inducer.

SUBMITTER: Carbone D

PROVIDER: S-EPMC10542626 | biostudies-literature | 2023 Oct

REPOSITORIES: biostudies-literature

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Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway.

Carbone Dalila D Gallo Carmela C Nuzzo Genoveffa G Barra Giusi G Dell'Isola Mario M Affuso Mario M Follero Olimpia O Albiani Federica F Sansone Clementina C Manzo Emiliano E d'Ippolito Giuliana G Fontana Angelo A

Natural products and bioprospecting 20231002 1

Immunogenic Cell Death (ICD) represents a mechanism of enhancing T cell-driven response against tumor cells. The process is enabled by release of damage-associated molecular patterns (DAMPs) and cytokines by dying cells. Based on molecular studies and clinical marker assessment, ICD can be a new target for cancer chemotherapy hitherto restricted to a few conventional anticancer drugs. In view of the development of small molecules in targeted cancer therapy, we reported the preliminary evidence o ...[more]

PMID: 37779162

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Project description:Regulated cell death (RCD) has always been considered a tolerogenic event. Immunogenic cell death (ICD) occurs as a consequence of tumour cell death accompanied by the release of damage-associated molecular patterns (DAMPs), triggering an immune response. ICD plays a major role in stimulating the function of the immune system in cancer during chemotherapy and radiotherapy. ICD can therefore represent one of the routes to boost anticancer immune responses. According to the recommendations of the Nomenclature Committee on Cell Death (2018), apoptosis (type I cell death) and necrosis (type II cell death) represent are not the only types of RCD, which also includes necroptosis, pyroptosis, ferroptosis and others. Specific downstream signalling molecules and death-inducing stimuli can regulate distinct forms of ICD, which develop and promote the immune cell response. Dying cells deliver different potential immunogenic signals, such as DAMPs, which are able to stimulate the immune system. The acute exposure of DAMPs can prime antitumour immunity by inducing activation of antigen-presenting cells (APC), such as dendritic cells (DC), leading to the downstream response by cytotoxic T cells and natural killer cells (NK). As ICD represents an important target to direct and develop new pharmacological interventions, the identification of bioactive natural products, which are endowed with low side effects, higher tolerability and preferentially inducing immunogenic programmed cell death, represents a priority in biomedical research. The ability of ICD to drive the immune response depends on two major factors, neither of which is intrinsic to cell death: 'Antigenicity and adjuvanticity'. Indeed, the use of natural ICD-triggering molecules, alone or in combination with different (immuno)therapies, can result in higher efficacy and tolerability. Here, we focused on natural (marine) compounds, particularly on marine microalgae derived molecules such as exopolysaccharides, sulphated polysaccharides, glycopeptides, glycolipids, phospholipids, that are endowed with ICD-inducing properties and sulfavants. Here, we discuss novel and repurposed small-molecule ICD triggers, as well as their ability to target important molecular pathways including the IL-6, TNF-α and interferons (IFNs), leading to immune stimulation, which could be used alone or in combinatorial immunotherapeutic strategies in cancer prevention and therapies.

Project description:Cancer immunotherapy including adoptive T cell therapy (ACT) is widely used in the clinic and is highly beneficial for patients with hematological malignancies; however, it remains a challenge to develop effective immunotherapy strategies for the treatment of solid cancers, due to the inefficiency of the immune response and the immunosuppressive tumor microenvironment (TME). Immunogenic cell death (ICD) converts dying cancer cells into a therapeutic vaccine and stimulate a systemic antigen-specific antitumor immune response, which can effectively subvert the immunosuppressive TME and enhance the efficiency of immune responses, relative to conventional immunotherapeutic regimens. However, the application of traditional inducers of ICD in anti-cancer immunotherapy has been limited because of low levels of ICD induction and a lack of tumor-targeting accumulation. Mitochondria are important for tumor-targeting strategies and have emerged as organelles with key roles in the immune system. We hypothesized that the alteration of mitochondria in cancer cells could be an important target for the development of an efficient ICD inducer for use in cancer immunotherapy. Here, we report the evaluation of a mitochondria-targeted small molecule, IR-780, that acts as an ICD inducer and exhibits exceptional antineoplastic activity. IR-780 specifically accumulated in tumor cells to elicit ICD in vitro and in vivo, effectively suppressed tumor growth and lung metastasis, and enhanced adoptive T-cell therapy effects against solid tumors in mouse models. These anticancer effects were linked to dendritic cell maturation and synergistic effector T cell priming and infiltration into tumors. The underlying mechanism involves the direct targeting of the mitochondria by IR-780, to destroy cancer cells, including drug-resistant cancer cells, leading to the full exposure of tumor-associated antigens (TAAs), thereby enhancing antigen-specific antitumor immune responses. These features of IR-780 suggest that it has the advantage of leading to complete TAA exposure and the stimulation of efficient antitumor immune responses in the TME. IR-780 has potential for use as a preparative ICD inducer, in combination with conventional immunostimulatory regimens for cancer immunotherapy, particularly in the context of solid tumor treatment.

Dataset Information

Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway.

Publications

Marine natural product lepadin A as a novel inducer of immunogenic cell death via CD91-dependent pathway.

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