Peripheral T-cell lymphomas (PTCL) are agressive lymphomas that develop from mature T cells. The most common PTCLs are genetically, molecularly, and clinically diverse and are generally associated with dismal outcomes. While Notch signaling plays a critically important role in both the development of immature T cells and their malignant transformation, its role in PTCL is poorly understood, despite the increasingly appreciated function of Notch in regulating the proliferation and differentiation of mature T cells. Here, we demonstrate that Notch receptors and their Delta-like family ligands (DLL1/DLL4) play a pathogenic role in PTCL. Notch1 activation was observed in common PTCL subtypes, including PTCL-NOS. In a large cohort of PTCL-NOS biopsies, Notch1 activation was significantly associated with surrogate markers of proliferation. Complementary genetically-engineered mouse models and spontaneous PTCL models were utilized to functionally examine the role of Notch signaling, and Notch1/Notch2 blockade and pan-Notch blockade using dominant negative MAML significantly impaired the proliferation of malignant T cells and PTCL progression in these models. Treatment with DLL1/DLL4 blocking antibodies established that Notch signaling is ligand dependent. Together, these findings reveal a role for ligand-dependent Notch signaling in driving peripheral T-cell lymphomagenesis.
The reciprocal relationship between malignant T cells and lymphoma-associated macrophages (LAM) within the tumor microenvironment (TME) is unique, as LAM are well poised to provide ligands for antigen-, costimulatory-, and cytokine receptors that promote T-cell lymphoma growth. Conversely, malignant T cells promote the functional polarization and homeostatic survival of LAM. Therefore, we sought to determine the extent to which LAM are a therapeutic vulnerability in these lymphomas, and to identify effective therapeutic strategies for their depletion. We utilized complementary genetically engineered mouse (GEM) models and primary peripheral T-cell lymphoma (PTCL) specimens to quantify LAM expansion and proliferation. A high-throughput screen was performed to identify targeted agents that effectively deplete LAM within the context of PTCL. We observed that LAM are dominant constituents of the TME in PTCL. Furthermore, their dominance was explained, at least in part, by their proliferation and expansion in response to PTCL-derived cytokines. Importantly, LAM are a true dependency in these lymphomas, as their depletion significantly impaired PTCL progression. These findings were extrapolated to a large cohort of human PTCL specimens where LAM proliferation was observed. A high-throughput screen demonstrated that PTCL-derived cytokines led to relative resistance to CSF-1R selective inhibitors, and culminated in the identification of dual CSF-1R/JAK inhibition as a novel therapeutic strategy to deplete LAM in these aggressive lymphomas. Malignant T cells promote the expansion and proliferation of LAM, which are a bone fide dependency in these lymphomas, and are effectively depleted with a dual CSF-1R/JAK inhibitor.
scite is a Brooklyn-based organization that helps researchers better discover and understand research articles through Smart Citations–citations that display the context of the citation and describe whether the article provides supporting or contrasting evidence. scite is used by students and researchers from around the world and is funded in part by the National Science Foundation and the National Institute on Drug Abuse of the National Institutes of Health.