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      Immune Checkpoints in Pediatric Solid Tumors: Targetable Pathways for Advanced Therapeutic Purposes

      review-article
      , , *
      Cells
      MDPI
      immune checkpoint inhibitors, pediatric solid tumor, immune suppression

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          Abstract

          The tumor microenvironment (TME) represents a complex network between tumor cells and a variety of components including immune, stromal and vascular endothelial cells as well as the extracellular matrix. A wide panel of signals and interactions here take place, resulting in a bi-directional modulation of cellular functions. Many stimuli, on one hand, induce tumor growth and the spread of metastatic cells and, on the other hand, contribute to the establishment of an immunosuppressive environment. The latter feature is achieved by soothing immune effector cells, mainly cytotoxic T lymphocytes and B and NK cells, and/or through expansion of regulatory cell populations, including regulatory T and B cells, tumor-associated macrophages and myeloid-derived suppressor cells. In this context, immune checkpoints (IC) are key players in the control of T cell activation and anti-cancer activities, leading to the inhibition of tumor cell lysis and of pro-inflammatory cytokine production. Thus, these pathways represent promising targets for the development of effective and innovative therapies both in adults and children. Here, we address the role of different cell populations homing the TME and of well-known and recently characterized IC in the context of pediatric solid tumors. We also discuss preclinical and clinical data available using IC inhibitors alone, in combination with each other or administered with standard therapies.

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          The blockade of immune checkpoints in cancer immunotherapy.

          Among the most promising approaches to activating therapeutic antitumour immunity is the blockade of immune checkpoints. Immune checkpoints refer to a plethora of inhibitory pathways hardwired into the immune system that are crucial for maintaining self-tolerance and modulating the duration and amplitude of physiological immune responses in peripheral tissues in order to minimize collateral tissue damage. It is now clear that tumours co-opt certain immune-checkpoint pathways as a major mechanism of immune resistance, particularly against T cells that are specific for tumour antigens. Because many of the immune checkpoints are initiated by ligand-receptor interactions, they can be readily blocked by antibodies or modulated by recombinant forms of ligands or receptors. Cytotoxic T-lymphocyte-associated antigen 4 (CTLA4) antibodies were the first of this class of immunotherapeutics to achieve US Food and Drug Administration (FDA) approval. Preliminary clinical findings with blockers of additional immune-checkpoint proteins, such as programmed cell death protein 1 (PD1), indicate broad and diverse opportunities to enhance antitumour immunity with the potential to produce durable clinical responses.
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            Nivolumab versus Docetaxel in Advanced Squamous-Cell Non–Small-Cell Lung Cancer

            New England Journal of Medicine, 373(2), 123-135
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              Combined Nivolumab and Ipilimumab or Monotherapy in Untreated Melanoma

              New England Journal of Medicine, 373(1), 23-34
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                Author and article information

                Contributors
                Role: Academic Editor
                Journal
                Cells
                Cells
                cells
                Cells
                MDPI
                2073-4409
                17 April 2021
                April 2021
                : 10
                : 4
                : 927
                Affiliations
                Laboratorio Cellule Staminali Post-Natali e Terapie Cellulari, IRCCS Istituto Giannina Gaslini, Via G. Gaslini 5, 16147 Genova, Italy; claudiacocco@ 123456gaslini.org (C.C.); fabiomorandi@ 123456gaslini.org (F.M.)
                Author notes
                [* ]Correspondence: irmaairoldi@ 123456gaslini.org ; Tel.: +39-010-5636-3535
                [†]

                These authors contributed equally to the work.

                Author information
                https://orcid.org/0000-0002-2849-7595
                Article
                cells-10-00927
                10.3390/cells10040927
                8074115
                ddc05257-4c94-4939-a18d-2a2413d034a5
                © 2021 by the authors.

                Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license ( https://creativecommons.org/licenses/by/4.0/).

                History
                : 31 March 2021
                : 14 April 2021
                Categories
                Review

                immune checkpoint inhibitors,pediatric solid tumor,immune suppression

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