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Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors.
- Source :
-
Oncotarget [Oncotarget] 2016 Apr 26; Vol. 7 (17), pp. 23282-99. - Publication Year :
- 2016
-
Abstract
- The tumor stroma, which is essential to support growth and metastasis of malignant cells, provides targets for active immunotherapy of cancer. Previous studies have shown that depleting fibroblast activation protein (FAP)-expressing stromal cells reduces tumor progression and concomitantly increases tumor antigen (TA)-specific T cell responses. However the underlying pathways remain ill defined. Here we identify that immunosuppressive cells (ISCs) from tumor-bearing mice impose metabolic stress on CD8+T cells, which is associated with increased expression of the co-inhibitor PD-1. In two mouse melanoma models, depleting FAP+ stroma cells from the tumor microenvironment (TME) upon vaccination with an adenoviral-vector reduces frequencies and functions of ISCs. This is associated with changes in the cytokine/chemokine milieu in the TME and decreased activity of STAT6 signaling within ISCs. Decreases in ISCs upon FAP+stromal cell depletion is associated with reduced metabolic stress of vaccine-induced tumor infiltrating CD8+T cells and their delayed progression towards functional exhaustion, resulting in prolonged survival of tumor-bearing mice.<br />Competing Interests: The authors declare that they have no conflict of interest.
- Subjects :
- Animals
Dendritic Cells immunology
Endopeptidases
Female
Genetic Vectors
Humans
Melanoma, Experimental metabolism
Melanoma, Experimental therapy
Mice
Mice, Inbred C57BL
Mice, Transgenic
Stromal Cells immunology
Tumor Cells, Cultured
CD8-Positive T-Lymphocytes immunology
Cancer Vaccines administration & dosage
Gelatinases metabolism
Immunosuppression Therapy
Melanoma, Experimental immunology
Membrane Proteins metabolism
Serine Endopeptidases metabolism
Tumor Microenvironment immunology
Subjects
Details
- Language :
- English
- ISSN :
- 1949-2553
- Volume :
- 7
- Issue :
- 17
- Database :
- MEDLINE
- Journal :
- Oncotarget
- Publication Type :
- Academic Journal
- Accession number :
- 26943036
- Full Text :
- https://doi.org/10.18632/oncotarget.7818