Obstacles to T cell migration in the tumor microenvironment |
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Affiliation: | 1. University of Michigan Medical School, Ann Arbor, Michigan;2. Morphomics Analysis Group, University of Michigan, Ann Arbor, Michigan;3. Department of Surgery, Dartmouth-Hitchcock Medical Center, Lebanon, New Hampshire;4. Department of Surgery, University of Michigan Health System, Ann Arbor, Michigan;5. Department of Medicine, Division of Hematology/Oncology, University of Michigan Health System, Ann Arbor, Michigan;6. Department of Radiology, University of Michigan Health System, 1500 E. Medical Center Dr. B2-A209P, Ann Arbor, MI 48108;7. Department of Urology, University of Michigan Health System, Ann Arbor, Michigan;8. Michigan Radiology Quality Collaborative, Ann Arbor, Michigan |
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Abstract: | These last years, significant progress has been made in the design of strategies empowering T cells with efficient anti-tumor activities. Hence, adoptive T cell therapy and the use of monoclonal antibodies against the immunosuppressive surface molecules CTLA-4 and PD-1 appear as the most promising immunotherapies against cancer. One of the challenges ahead is to render these therapeutic interventions even more effective as a still elevated fraction of cancer patients is refractory to these treatments. A frequently overlooked determinant of the success of T cell-based immunotherapy relates to the ability of effector T cells to migrate into and within tumors, as well as to have access to tumor antigens. Here, we will focus on recent advances in understanding T cell trafficking into and within tumors. Both chemoattractant molecules and structural determinants are essential for regulating T cell motile behavior along with cellular interactions-mediated antigen recognition. In addition, we will review evidence that the microenvironment of advanced tumors creates multiple obstacles limiting T cells from migrating and making contact with their malignant targets. We will particularly focus on the extracellular matrix and tumor-associated macrophages that make tumors a hostile environment for T cell ability to contact and kill malignant cells. Finally, we will discuss possible strategies to restore a tumor microenvironment more favorable to T cell migration and functions with a special emphasis on approaches targeting the dysregulated extracellular matrix of growing tumors. |
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Keywords: | Cancer T cells Immunotherapy Migration Extracellular matrix Macrophages |
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