Depletion of FAP+ cells reduces immunosuppressive cells and improves metabolism and functions CD8+T cells within tumors

// Ying Zhang 1, 2 , Hildegund C.J. Ertl 2 1 Gene Therapy and Vaccines Program, University of Pennsylvania, Philadelphia, Pennsylvania, USA 2 The Wistar Institute, Philadelphia, Pennsylvania, USA Correspondence to: Hildegund C.J. Ertl, e-mail: ertl@wistar.upenn.edu Keywords: FAP + fibroblasts, cancer vaccine, metabolic stress, T cell exhaustion, immunosuppressive cells Received: December 22, 2015     Accepted: February 14, 2016     Published: March 01, 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.