A three‐signal model of T‐cell lymphoma pathogenesis

Abstract

T-cell lymphoma pathogenesis and classification have, until recently, remained enigmatic. Recently performed whole-exome sequencing and gene-expression profiling studies have significant implications for their classification and treatment. Recurrent genetic modifications in antigen (“signal 1”), costimulatory (“signal 2”), or cytokine receptors (“signal 3”), and the tyrosine kinases and other signaling proteins they activate, have emerged as important therapeutic targets in these lymphomas. Many of these genetic modifications do not function in a cell-autonomous manner, but require the provision of ligand(s) by constituents of the tumor microenvironment, further supporting the long-appreciated view that these lymphomas are dependent upon and driven by their microenvironment. Therefore, the seemingly disparate fields of genomics and immunology are converging. A unifying “3 signal model” for T-cell lymphoma pathogenesis that integrates these findings will be presented, and its therapeutic implications briefly reviewed.

Integrated mate-pair and RNA sequencing identifies novel, targetable gene fusions in peripheral T-cell lymphoma

“…32,48 More broadly, these findings suggest the importance of TCR signaling as a key pathway involved in lymphomagenesis, 60 as has been demonstrated in mice 61 and is evidenced further by other genes altered by various mechanisms in PTCLs, including rearrangements of SYK, copy number gains of ITK, and point mutations of FYN. 16,49,57,62 These potentially targetable molecular alterations show promise for advances analogous to those resulting from elucidation of dysregulated B-cell receptor signaling in B-cell NHLs.…”

A single center phase II study of ixazomib in patients with relapsed or refractory cutaneous or peripheral T‐cell lymphomas

“…including p53 1, 9 ] and the expression of multidrug resistance proteins likely contribute to resistance. 10 Constituents of the tumor microenvironment (TME), particularly lymphoma-associated macrophages, may also promote resistance to chemotherapy, 11 likely due to the provision of cell surface ligands or cytokines that activate signaling pathways implicated in chemotherapy resistance [reviewed in 12 ]. A limited number of transcriptional regulators known to regulate the differentiation, proliferation, and survival of normal T cells have also been implicated in disease pathogenesis and chemotherapy resistance, chief among these is the NF-κB family of transcription factors.…”

Challenges and opportunities for checkpoint blockade in T-cell lymphoproliferative disorders

“…Conversely, amplification of the JAK2 locus and enhanced JAK/STAT signaling promotes PD-L1 expression in selected B-cell malignancies [6, 45]. Therefore, gain-of-function mutations and other genetic alterations that promote JAK/STAT signaling in selected PTCL subtypes may confer susceptibility to CPB [reviewed in [46]]. Of course, the incorporation of genomic data in future and ongoing CPB trials will be required to address this question and may improve the ability to identify “exceptional responders”.…”

“…The extent to which these B cells have regulatory properties is poorly understood [57]. Therefore, in addition to structural alterations in secondary lymphoid organs, the “cell of origin” from which a malignant T cell is derived dramatically alters the TME in a manner that is likely relevant for CPB and other immunomodulatory therapies [46]. …”

“…The role of these novel agents, and their targets, in the T-cell lymphoproliferative disorders is poorly understood, but is the subject of ongoing pre-clinical and clinical studies [46, 86]. More recently, we observed that TCR activation in primary T-cell lymphoma cells had a profound effect on gene expression, as ≈ 1000 genes were significantly upregulated following TCR engagement, including those that regulate cell growth and survival [87].…”