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      3D models in the new era of immune oncology: focus on T cells, CAF and ECM

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          Abstract

          Immune checkpoint inhibitor therapy has changed clinical practice for patients with different cancers, since these agents have demonstrated a significant improvement of overall survival and are effective in many patients. However, an intrinsic or acquired resistance frequently occur and biomarkers predictive of responsiveness should help in patient selection and in defining the adequate treatment options. A deep analysis of the complexity of the tumor microenvironment is likely to further advance the field and hopefully identify more effective combined immunotherapeutic strategies. Here we review the current knowledge on tumor microenvironment, focusing on T cells, cancer associated fibroblasts and extracellular matrix. The use of 3D cell culture models to resemble tumor microenvironment landscape and to screen immunomodulatory drugs is also reviewed.

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          Most cited references96

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          Tensional homeostasis and the malignant phenotype.

          Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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            Why don't we get more cancer? A proposed role of the microenvironment in restraining cancer progression.

            Tumors are like new organs and are made of multiple cell types and components. The tumor competes with the normal microenvironment to overcome antitumorigenic pressures. Before that battle is won, the tumor may exist within the organ unnoticed by the host, referred to as 'occult cancer'. We review how normal tissue homeostasis and architecture inhibit progression of cancer and how changes in the microenvironment can shift the balance of these signals to the procancerous state. We also include a discussion of how this information is being tailored for clinical use.
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              Generation of Tumor-Reactive T Cells by Co-culture of Peripheral Blood Lymphocytes and Tumor Organoids

              Cancer immunotherapies have shown substantial clinical activity for a subset of patients with epithelial cancers. Still, technological platforms to study cancer T-cell interactions for individual patients and understand determinants of responsiveness are presently lacking. Here, we establish and validate a platform to induce and analyze tumor-specific T cell responses to epithelial cancers in a personalized manner. We demonstrate that co-cultures of autologous tumor organoids and peripheral blood lymphocytes can be used to enrich tumor-reactive T cells from peripheral blood of patients with mismatch repair-deficient colorectal cancer and non-small-cell lung cancer. Furthermore, we demonstrate that these T cells can be used to assess the efficiency of killing of matched tumor organoids. This platform provides an unbiased strategy for the isolation of tumor-reactive T cells and provides a means by which to assess the sensitivity of tumor cells to T cell-mediated attack at the level of the individual patient.
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                Author and article information

                Contributors
                francesca.dimodugno@ifo.gov.it
                cristinacolosi@gmail.com
                paola.trono@ifo.gov.it
                giuseppe.antonacci.iit@gmail.com
                giancarlo.ruocco@iit.it
                paola.nistico@ifo.gov.it
                Journal
                J Exp Clin Cancer Res
                J. Exp. Clin. Cancer Res
                Journal of Experimental & Clinical Cancer Research : CR
                BioMed Central (London )
                0392-9078
                1756-9966
                22 March 2019
                22 March 2019
                2019
                : 38
                : 117
                Affiliations
                [1 ]ISNI 0000 0004 1760 5276, GRID grid.417520.5, Unit of Tumor Immunology and Immunotherapy, Department of Research, Advanced Diagnostics, and Technological Innovation, Translational Research Area, , IRCCS-Regina Elena National Cancer Institute, ; via Elio Chianesi 53, 00144 Rome, Italy
                [2 ]ISNI 0000 0004 1764 2907, GRID grid.25786.3e, Center for Life Nano Science@Sapienza, , Istituto Italiano di Tecnologia, ; Viale Regina Elena 291, 00161 Rome, Italy
                Article
                1086
                10.1186/s13046-019-1086-2
                6429763
                30898166
                dede9692-0aa2-40b3-8216-4d1762bec282
                © The Author(s). 2019

                Open AccessThis article is distributed under the terms of the Creative Commons Attribution 4.0 International License ( http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver ( http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.

                History
                : 7 January 2019
                : 6 February 2019
                Funding
                Funded by: FundRef http://dx.doi.org/10.13039/501100005010, Associazione Italiana per la Ricerca sul Cancro;
                Award ID: IG 15224
                Award ID: 5×1000, 12182
                Award Recipient :
                Categories
                Review
                Custom metadata
                © The Author(s) 2019

                Oncology & Radiotherapy
                tumor microenvironment,immune oncology,3d culture models,t cells,cancer associated fibroblasts,extracellular matrix

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