Abstract IA18: Tumor stroma: Immunomodulatory functions and a target of immunotherapy

Abstract

Abstract Many solid tumors in human exhibit highly desmoplastic stroma, the result of a fibroproliferative response and accumulation of provisional matrix. Stroma plays myriad functions in cancer. Cancer associated fibroblasts (CAFs) and the extracellular matrix (ECM) they deposit act as a scaffold that imposes architectural order and defines the spatial relationship of neoplastic cells and their precursors to a multitude of other non-transformed components in the microenvironment of both primary tumors and metastases. Reactive stroma is also enriched in growth and angiogenic factors, presents chemoattractants that promote the recruitment of bone marrow-derived cells, and can modulate inflammatory and immune cell function, all of which can contribute to its tumor permissive nature relative to normal stroma. CAFs however are heterogeneous and their phenotypic and functional diversity remain ill-defined. Furthermore, adaptation to the dynamic and regionally diverse nature of the microenvironment and cross-talk with tumor cells and infiltrating cells can drive co-evolution of the phenotype and function of stromal cells and matrix architecture adding to the spatial and temporal complexity of the stromal compartment. The expression of smooth muscle actin (SMA) is a well-recognized and defining marker of myofibroblasts but the proportion of CAFs that express this marker varies between tumor types and between individual tumors of any particular tumor type. A significant proportion of CAFs in virtually all human carcinomas however, express the cell surface protease fibroblast activation protein (FAP) that is also expressed on a subset of M2-like tumor-associated macrophages. SMA and FAP expressing populations overlap to varying degrees in different tumors and tumor types. We developed an adoptive cell transfer approach employing chimeric antigen receptor (CAR) expressing T cells to define the function of FAP expressing cells in various tumor types. Our studies indicate that FAP+ cells are required for the generation and maintenance of desmoplastic stroma and that depletion of FAP+ cells can inhibit tumor growth through both immune-dependent and immune-independent mechanisms. Moreover, we found that the anti-tumor activity of FAP- CAR T cells and the mechanisms by which FAP-targeted CAR T cells inhibited growth and progression in different tumor models was a function of the degree of desmoplasia and tumor immunogenicity. Taken together with data recently published by others, our data suggest that at least in models of pancreatic cancer, a subset of highly proliferating SMA+ cells and FAP+ cells play distinct and possibly opposing roles in tumor progression and this must be taken into account in the rational design of stroma targeted therapies. Citation Format: Ellen Puré. Tumor stroma: Immunomodulatory functions and a target of immunotherapy. [abstract]. In: Proceedings of the CRI-CIMT-EATI-AACR Inaugural International Cancer Immunotherapy Conference: Translating Science into Survival; September 16-19, 2015; New York, NY. Philadelphia (PA): AACR; Cancer Immunol Res 2016;4(1 Suppl):Abstract nr IA18.