Abstract 3187: Depleting cells expressing fibroblast activation protein disrupts tumor-promoting desmoplasia

Abstract

Abstract Solid tumors recruit and activate a heterogeneous population of non-transformed stromal cells (CASCs) in the tumor microenvironment (TME). There has been growing interest in the field to develop strategies to treat cancer and circumvent resistance to therapy by targeting CASCs. Defining the phenotypic subsets and the function of distinct subpopulations including myofibroblasts (defined by the expression of SMA) and the overlapping but distinct population of CASCs expressing Fibroblast Activation Protein (FAP) will be critical to informing the rational design of stromal-targeted therapies. FAP is a membrane serine protease that is selectively up-regulated in CASCs including cancer-associated fibroblasts (CAFs), mesenchymal stem cells (MSCs), and a subset of M2 macrophages, of virtually all common human epithelial cancers. Based on its selective expression on CASCs across a wide range of tumor types, we engineered FAP-specific chimeric antigen receptor expressing T cells (FAP-CAR T cells) and adoptively transferred them into tumor bearing mice to: 1) define the requirement for FAP+ cells for the accumulation and maintenance of a desmoplastic matrix; 2) define the relationship between the degree of desmoplasia, the capacity of FAP-CAR T cells to disrupt the tumor stroma and to inhibit tumor growth; and 3) determine whether FAP-CAR T cells can inhibit tumor growth through immune independent mechanisms. We found that FAP+ CACSs are responsible for maintaining the desmoplastic response and that conditional depletion following treatment with FAP-CAR T cells inhibits growth of human lung cancer xenografts and mouse pancreatic tumors in an immune-independent fashion. Taken together with recently published studies (1-3), our data provide important distinctions between the function of FAP+ CASCs and SMA+ myofibroblasts and provide support for further development of FAP+ stromal cell-targeted therapies for a wide range of solid tumors. Reference: 1. Feig, C., Jones, J. O., Kraman, M., Wells, R. J., Deonarine, A., Chan, D. S., et al. (2013). Targeting CXCL12 from FAP-expressing carcinoma-associated fibroblasts synergizes with anti-PD-L1 immunotherapy in pancreatic cancer. Proc Natl Acad Sci USA 110, 20212-20217. 2. Ozdemir, B. C., Pentcheva-Hoang, T., Carstens, J. L., Zheng, X., Wu, C. C., Simpson, T. R., et al. (2014). Depletion of carcinoma-associated fibroblasts and fibrosis induces immunosuppression and accelerates pancreas cancer with reduced survival. Cancer Cell 25, 719-734. 3. Wang, L. C., Lo, A., Scholler, J., Sun, J., Majumdar, R. S., Kapoor, V., et al. (2014). Targeting fibroblast activation protein in tumor stroma with chimeric antigen receptor T cells can inhibit tumor growth and augment host immunity without severe toxicity. Cancer Immunol Res 2, 154-166. Citation Format: Albert Lo, Liang-Chuan S Wang, John Scholler, James Monslow, Diana Avery, Rebecca A. Evans, David J. Bajor, Amy C. Durham, Elizabeth L. Buza, Robert H. Vonderheide, Carl H. June, Steven M. Albelda, Ellen Puré. Depleting cells expressing fibroblast activation protein disrupts tumor-promoting desmoplasia. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 3187. doi:10.1158/1538-7445.AM2015-3187