title: Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors.
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.
authors.affiliation: Gene Therapy and Vaccines Program, University of Pennsylvania, Philadelphia, Pennsylvania, USA.|The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Ying
authors.initials: Y
authors.lastname: Zhang
authors.affiliation: The Wistar Institute, Philadelphia, Pennsylvania, USA.
authors.forename: Hildegund C J
authors.initials: HC
authors.lastname: Ertl
mesh_terms: D000818:Animals; D018414:CD8-Positive T-Lymphocytes / Q000276:immunology*; D019496:Cancer Vaccines / Q000008:administration & dosage*; D003713:Dendritic Cells / Q000276:immunology; D010450:Endopeptidases; D005260:Female; D018093:Gelatinases / Q000378:metabolism*; D005822:Genetic Vectors; D006801:Humans; D007165:Immunosuppression Therapy; D008546:Melanoma, Experimental / Q000276:immunology* / Q000378:metabolism / Q000628:therapy; D008565:Membrane Proteins / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D008822:Mice, Transgenic; D012697:Serine Endopeptidases / Q000378:metabolism*; D017154:Stromal Cells / Q000276:immunology; D014407:Tumor Cells, Cultured; D059016:Tumor Microenvironment / Q000276:immunology*; D000099167:Fibroblast Activation Protein Alpha
chemical_list: D019496:Cancer Vaccines; D010450:Endopeptidases; D018093:Gelatinases; D008565:Membrane Proteins; D012697:Serine Endopeptidases; D000099167:Fibroblast Activation Protein Alpha
keywords: FAP+ fibroblasts; T cell exhaustion; cancer vaccine; immunosuppressive cells; metabolic stress