title: Obstacles Posed by the Tumor Microenvironment to T cell Activity: A Case for Synergistic Therapies.
abstract: T cell dysfunction in solid tumors results from multiple mechanisms. Altered signaling pathways in tumor cells help produce a suppressive tumor microenvironment enriched for inhibitory cells, posing a major obstacle for cancer immunity. Metabolic constraints to cell function and survival shape tumor progression and immune cell function. In the face of persistent antigen, chronic T cell receptor signaling drives T lymphocytes to a functionally exhausted state. Here we discuss how the tumor and its microenvironment influences T cell trafficking and function with a focus on melanoma, and pancreatic and ovarian cancer, and discuss how scientific advances may help overcome these hurdles.
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Mail Stop D3-100, P.O. Box 19024, Seattle, WA 98109, USA; Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Departments of Medicine/Oncology and Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA.
authors.forename: Kristin G
authors.initials: KG
authors.lastname: Anderson
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Mail Stop D3-100, P.O. Box 19024, Seattle, WA 98109, USA; Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA. Electronic address: istromne@fredhutch.org.
authors.forename: Ingunn M
authors.initials: IM
authors.lastname: Stromnes
authors.affiliation: Clinical Research Division, Fred Hutchinson Cancer Research Center, Mail Stop D3-100, P.O. Box 19024, Seattle, WA 98109, USA; Program in Immunology, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Departments of Medicine/Oncology and Immunology, University of Washington School of Medicine, Seattle, WA 98109, USA. Electronic address: pgreen@u.washington.edu.
authors.forename: Philip D
authors.initials: PD
authors.lastname: Greenberg
mesh_terms: D000596:Amino Acids / Q000378:metabolism; D003602:Cytotoxicity, Immunologic; D005227:Fatty Acids / Q000378:metabolism; D016158:Genes, p53; D005947:Glucose / Q000378:metabolism; D006801:Humans; D019344:Lactic Acid / Q000378:metabolism; D009369:Neoplasms / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D011948:Receptors, Antigen, T-Cell / Q000502:physiology; D013601:T-Lymphocytes / Q000276:immunology*; D059016:Tumor Microenvironment
chemical_list: D000596:Amino Acids; D005227:Fatty Acids; D011948:Receptors, Antigen, T-Cell; D019344:Lactic Acid; D005947:Glucose
keywords: T cell dysfunction; TME; adoptive T cell therapy; genetic engineering; immunotherapy; tumor microenvironment