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      On the Biology and Therapeutic Modulation of Macrophages and Dendritic Cells in Cancer

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          Abstract

          Myeloid cells represent a dominant cellular compartment of tumor lesions and play key roles in tumor inception, progression, metastasis, and response to treatment. Mononuclear phagocytes (MNPs), which include dendritic cells and macrophages, are unique among myeloid cells, as they not only shape both the broader composition and state of the tumor microenvironment but can also specifically instruct cancer-specific, T cell–mediated tumor cell killing, making them especially attractive targets for cancer treatment. Although MNPs remain difficult to modulate therapeutically, our understanding of MNP biology in the antitumor immune response has expanded significantly, offering hope for new possibilities in cancer immunotherapy. Here, we review the recent advances in our study of the cellular identity, molecular diversity, and spatial organization of MNPs in tumors, and we discuss the importance of tailoring therapeutic strategies to incorporate these new insights into cancer treatment design.

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          Understanding the tumor immune microenvironment (TIME) for effective therapy

          The clinical successes in immunotherapy have been both astounding and at the same time unsatisfactory. Countless patients with varied tumor types have seen pronounced clinical response with immunotherapeutic intervention; however, many more patients have experienced minimal or no clinical benefit when provided the same treatment. As technology has advanced, so has the understanding of the complexity and diversity of the immune context of the tumor microenvironment and its influence on response to therapy. It has been possible to identify different subclasses of immune environment that have an influence on tumor initiation and response and therapy; by parsing the unique classes and subclasses of tumor immune microenvironment (TIME) that exist within a patient’s tumor, the ability to predict and guide immunotherapeutic responsiveness will improve, and new therapeutic targets will be revealed.
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            A framework for advancing our understanding of cancer-associated fibroblasts

            Cancer-associated fibroblasts (CAFs) are a key component of the tumour microenvironment with diverse functions, including matrix deposition and remodelling, extensive reciprocal signalling interactions with cancer cells and crosstalk with infiltrating leukocytes. As such, they are a potential target for optimizing therapeutic strategies against cancer. However, many challenges are present in ongoing attempts to modulate CAFs for therapeutic benefit. These include limitations in our understanding of the origin of CAFs and heterogeneity in CAF function, with it being desirable to retain some antitumorigenic functions. On the basis of a meeting of experts in the field of CAF biology, we summarize in this Consensus Statement our current knowledge and present a framework for advancing our understanding of this critical cell type within the tumour microenvironment.
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              Type, density, and location of immune cells within human colorectal tumors predict clinical outcome.

              The role of the adaptive immune response in controlling the growth and recurrence of human tumors has been controversial. We characterized the tumor-infiltrating immune cells in large cohorts of human colorectal cancers by gene expression profiling and in situ immunohistochemical staining. Collectively, the immunological data (the type, density, and location of immune cells within the tumor samples) were found to be a better predictor of patient survival than the histopathological methods currently used to stage colorectal cancer. The results were validated in two additional patient populations. These data support the hypothesis that the adaptive immune response influences the behavior of human tumors. In situ analysis of tumor-infiltrating immune cells may therefore be a valuable prognostic tool in the treatment of colorectal cancer and possibly other malignancies.
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                Author and article information

                Journal
                Annual Review of Cancer Biology
                Annu. Rev. Cancer Biol.
                Annual Reviews
                2472-3428
                2472-3428
                April 11 2023
                April 11 2023
                : 7
                : 1
                : 291-311
                Affiliations
                [1 ]Marc and Jennifer Lipschultz Precision Immunology Institute, The Tisch Cancer Institute, and Department of Oncological Sciences, Icahn School of Medicine at Mount Sinai, New York, NY, USA;
                [2 ]Division of Hematology/Oncology, Center for Thoracic Oncology, and Early-Phase Trials Unit, Icahn School of Medicine at Mount Sinai, New York, NY, USA
                Article
                10.1146/annurev-cancerbio-061521-085949
                2d4f7cb4-1c5f-4349-9e4a-33d951aa21f3
                © 2023

                http://creativecommons.org/licenses/by/4.0/

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