Notch ligands as oncogenic drivers and therapeutic targets in T-cell lymphomas

Peripheral T-cell lymphomas (PTCL), derived from mature T cells, are aggressive malignancies for which existing therapies are suboptimal, as the median overall survival of patients with relapsed/refractory disease is <6 months. These dismal outcomes are explained, at least in part, by an intrinsic resistance to conventional chemotherapeutic approaches and a poor understanding of recurrent, and therapeutically targetable, oncogenic drivers. Despite their genetic and molecular heterogeneity, most PTCL remain dependent upon their microenvironment, as constituents of the tumor microenvironment (TME) promote the growth, survival, and chemotherapy resistance of malignant T cells through trophic factors. Therefore, improved understanding of the trophic factors available to PTCL within the TME, and the cells that provide them, may unveil novel therapeutic strategies. Notch signaling, triggered by ligands presented by non-hematopoietic stromal cells, plays a critically important role in the development, differentiation, and function of conventional (non-malignant) T cells. Utilizing relevant and complementary genetically engineered mouse (GEM) models and primary PTCL specimens, we have discovered that Notch activation is highly recurrent in PTCL, not otherwise specified (PTCL, NOS). When activated, Notch signaling is associated with significant transcriptional reprogramming, PTCL proliferation, and a TME rich in fibroblastic reticular cells (FRC), which are specialized stromal cells required for the presentation of Notch ligands to conventional T cells in secondary lymphoid organs. Our preliminary data, utilizing complementary pharmacologic (i.e. antibody-based, and thus clinically translatable) and genetic approaches demonstrate that Notch signaling is an oncogenic driver in PTCL. Therefore, our overall objective in this application, bolstered by our preliminary data, is to identify the oncogenic Notch ligand(s) and the stromal cells that present them, and further characterize the transcriptional programs that they instigate, in PTCL. This objective will be achieved by addressing our central hypothesis that non-mutational, stromal cell- and ligand- dependent Notch signaling is a significant and therapeutically targetable oncogenic driver in mature T-cell lymphomas.