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      Longitudinal Intravital Imaging of Tumor-Infiltrating Lymphocyte Motility in Breast Cancer Models

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          Abstract

          Immunoreactive dynamics of tumor-infiltrating lymphocytes (TILs) within the tumor microenvironment in breast cancer are not well understood. This study aimed to investigate the spatiotemporal cellular dynamics of TILs in breast cancer models. Breast cancer cells were implanted into the dorsal skinfold chamber of BALB/c nude mice, and T lymphocytes were adoptively transferred. Longitudinal intravital imaging was performed, and the spatiotemporal dynamics of TILs were assessed. In the 4T1 model, TILs progressively exhibited increased motility, and their motility inside the tumor was significantly higher than that outside the tumor. In the MDA-MB-231 model, the motility of TILs progressively decreased after an initial increase. TIL motility in the MDA-MB-231 and MCF-7 models differed significantly, suggesting an association between programmed death-ligand 1 expression levels and TIL motility, which warrants further investigation. Furthermore, intravital imaging of TILs can be a useful method for addressing dynamic interactions between TILs and breast cancer cells.

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          Most cited references23

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          Innate and adaptive immune cells in the tumor microenvironment.

          Most tumor cells express antigens that can mediate recognition by host CD8(+) T cells. Cancers that are detected clinically must have evaded antitumor immune responses to grow progressively. Recent work has suggested two broad categories of tumor escape based on cellular and molecular characteristics of the tumor microenvironment. One major subset shows a T cell-inflamed phenotype consisting of infiltrating T cells, a broad chemokine profile and a type I interferon signature indicative of innate immune activation. These tumors appear to resist immune attack through the dominant inhibitory effects of immune system-suppressive pathways. The other major phenotype lacks this T cell-inflamed phenotype and appears to resist immune attack through immune system exclusion or ignorance. These two major phenotypes of tumor microenvironment may require distinct immunotherapeutic interventions for maximal therapeutic effect.
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            The evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer: recommendations by an International TILs Working Group 2014.

            The morphological evaluation of tumor-infiltrating lymphocytes (TILs) in breast cancer (BC) is gaining momentum as evidence strengthens for the clinical relevance of this immunological biomarker. Accumulating evidence suggests that the extent of lymphocytic infiltration in tumor tissue can be assessed as a major parameter by evaluation of hematoxylin and eosin (H&E)-stained tumor sections. TILs have been shown to provide prognostic and potentially predictive value, particularly in triple-negative and human epidermal growth factor receptor 2-overexpressing BC. A standardized methodology for evaluating TILs is now needed as a prerequisite for integrating this parameter in standard histopathological practice, in a research setting as well as in clinical trials. This article reviews current data on the clinical validity and utility of TILs in BC in an effort to foster better knowledge and insight in this rapidly evolving field, and to develop a standardized methodology for visual assessment on H&E sections, acknowledging the future potential of molecular/multiplexed approaches. The methodology provided is sufficiently detailed to offer a uniformly applied, pragmatic starting point and improve consistency and reproducibility in the measurement of TILs for future studies. © The Author 2014. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.
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              Adoptive cell transfer as personalized immunotherapy for human cancer.

              Adoptive cell therapy (ACT) is a highly personalized cancer therapy that involves administration to the cancer-bearing host of immune cells with direct anticancer activity. ACT using naturally occurring tumor-reactive lymphocytes has mediated durable, complete regressions in patients with melanoma, probably by targeting somatic mutations exclusive to each cancer. These results have expanded the reach of ACT to the treatment of common epithelial cancers. In addition, the ability to genetically engineer lymphocytes to express conventional T cell receptors or chimeric antigen receptors has further extended the successful application of ACT for cancer treatment. Copyright © 2015, American Association for the Advancement of Science.
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                Author and article information

                Journal
                J Breast Cancer
                J Breast Cancer
                JBC
                Journal of Breast Cancer
                Korean Breast Cancer Society
                1738-6756
                2092-9900
                October 2021
                08 September 2021
                : 24
                : 5
                : 463-473
                Affiliations
                [1 ]Department of Emergency Medicine, Seoul National University Bundang Hospital (SNUBH), Seongnam, Korea.
                [2 ]Department of Emergency Medicine, Seoul National University College of Medicine, Seoul, Korea.
                [3 ]Graduate School of Nanoscience and Technology, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
                [4 ]KI for Health Science and Technology (KIHST), Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
                [5 ]Graduate School of Medical Science and Engineering, Korea Advanced Institute of Science and Technology (KAIST), Daejeon, Korea.
                [6 ]Division of Rheumatology, Department of Internal Medicine, Gyeongsang National University School of Medicine, Jinju, Korea.
                Author notes
                Correspondence to You Hwan Jo. Department of Emergency Medicine, Seoul National University Bundang Hospital (SNUBH), 82 Gumi-ro 173beon-gil, Bundang-gu, Seongnam 13620, Korea. drakejo@ 123456snubh.org
                Author information
                https://orcid.org/0000-0001-7525-9189
                https://orcid.org/0000-0003-3438-9344
                https://orcid.org/0000-0002-8016-8385
                https://orcid.org/0000-0001-9456-1869
                https://orcid.org/0000-0003-3597-3593
                https://orcid.org/0000-0003-3744-8522
                https://orcid.org/0000-0002-2203-6886
                https://orcid.org/0000-0003-2983-196X
                https://orcid.org/0000-0002-0574-1372
                https://orcid.org/0000-0002-4955-523X
                https://orcid.org/0000-0002-3869-8008
                https://orcid.org/0000-0002-0277-0987
                https://orcid.org/0000-0003-2429-4085
                https://orcid.org/0000-0001-6363-7736
                https://orcid.org/0000-0001-8388-1840
                https://orcid.org/0000-0002-9507-7603
                Article
                10.4048/jbc.2021.24.e40
                8561133
                34652077
                9eaaa08a-36aa-483b-ba19-a5779e5b298d
                © 2021 Korean Breast Cancer Society

                This is an Open Access article distributed under the terms of the Creative Commons Attribution Non-Commercial License ( https://creativecommons.org/licenses/by-nc/4.0/) which permits unrestricted non-commercial use, distribution, and reproduction in any medium, provided the original work is properly cited.

                History
                : 30 April 2021
                : 20 August 2021
                : 05 September 2021
                Funding
                Funded by: Seoul National University Bundang Hospital
                Award ID: 14-2020-018
                Funded by: National Research Foundation of Korea, CrossRef https://doi.org/10.13039/501100003725;
                Award ID: NRF-2020R1F1A1058381
                Award ID: NRF-2020R1A2C2013095
                Award ID: NRF-2020R1A2C3005694
                Categories
                Brief Communication

                Oncology & Radiotherapy
                breast neoplasms,cell movement,intravital microscopy,lymphocytes, tumor-infiltrating,programmed cell death 1 receptor

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