Targeting Lymphoma-associated Macrophage Expansion via CSF1R/JAK Inhibition is a Therapeutic Vulnerability in Peripheral T-cell Lymphomas

Abstract

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.

Extranodal lymphoma: pathogenesis, diagnosis and treatment

“…The JAK/STAT pathway mediates the transmission of signals from cytokines and growth factors. Dysregulation of this pathway has been observed in extranodal lymphomas, including mucosa-associated lymphoid tissue (MALT) lymphomas, natural killer/T-cell lymphoma (nasal type, NKTCL-NT) [ 13 , 19 ], primary central nervous system lymphoma (PCNSL) [ 20 ] and peripheral T cell lymphoma (PTCL) [ 21 , 22 ]. The JAK/STAT pathway is associated with immune homeostasis, inflammation, cell proliferation, apoptosis and differentiation in extranodal lymphoma [ 21 ].…”

“…Inhibitors targeting JAK kinases have shown promising results. The JAK2/FLT3 fusion inhibitor pacritinib has demonstrated preclinical safety and efficacy [ 22 ]. The JAK3 inhibitor tofacitinib has shown therapeutic effects in PTCL [ 24 ] and NKTCL [ 19 ].…”