PROJECT ABSTRACT The T-cell lymphomas (TCL) are an area of unmet medical need as patients, particularly those with relapsed or refractory disease, are rarely cured with existing therapies. We, and others, have shown that antigen-, costimulation-, and cytokine-dependent signaling cooperatively promote the growth and survival of malignant T cells and confers their resistance to conventional chemotherapy. These signaling cascades are propagated by highly recurrent gain-of-function mutations in relevant kinases and by exogenous ligands provided by constituents of the tumor microenvironment (TME), including lymphoma-associated macrophages (LAM). Early phase clinical trials investigating tyrosine-kinase inhibitors (TKI) selective for relevant targets have been completed (or are ongoing), but most responses observed with these agents are partial and rarely durable. The genetic and molecular heterogeneity associated with the TCL and the cooperativity (and partial redundancies) among signaling pathways may explain the suboptimal activity associated with many targeted agents. Constituents of the TME, particularly LAM, create a niche that promotes TCL growth and survival both directly, by providing exogenous ligands for TCL-associated antigen, costimulatory, and cytokine receptors, and indirectly by suppressing host anti-tumor immunity. Therefore, an alternative, and potentially complementary, therapeutic approach is to target LAM. Efforts to deplete tumor-associated macrophages have been largely devoted to colony-stimulating factor-1 receptor (CSF-1R) antagonists, as current dogma suggests that this is the dominant homeostatic cytokine required for the survival of tissue resident macrophages. However, our own preliminary data challenges this conception, at least in a TCL context. Pexidartinib, for example, is a selective, and FDA-approved, CSF-1R TKI, to which TCL-associated macrophages are largely resistant. As LAM play a central role in TCL pathogenesis, one of our long-term goals is to develop novel, targeted therapies that impair their expansion, survival, and functional polarization. With that goal in mind, we performed an unbiased, high- throughput screen with almost 200 targeted agents, and discovered that TCL-associated macrophages, while resistant to multiple selective CSF-1R antagonists, were highly sensitive to pacritinib. Pacritinib is a safe, well tolerated, oral Janus family kinase (JAK) inhibitor that has been investigated in multiple phase I, II, and III studies (largely in myeloproliferative neoplasms). In addition to inhibiting multiple JAKs (JAK2, TYK2, JAK3), we have shown that pacritinib inhibits CSF-1R and Src family kinases at clinically achievable concentrations, both of which are highly relevant targets in TCL. Therefore, our overarching premise, is that inhibition of multiple, highly relevant kinases with both cell-autonomous and non-cell-autonomous roles in TCL pathogenesis is an attractive, but largely unexplored, therapeutic st...