Noncanonical effector functions of the T-memory–like T-PLL cell are shaped by cooperative TCL1A and TCR signaling

Oberbeck, S. ; Schrader, A. ; Warner, K. ; Jungherz, D. ; Crispatzu, G. ; von Jan, J. ; Chmielewski, M. ; Ianevski, A.

; Diebner, H. H.

; Mayer, P. ; Kondo Ados, A. ; Wahnschaffe, L. ; Braun, T. ; Müller, T. A. ; Wagle, P. ; Bouska, A. ; Neumann, T. ; Pützer, S. ; Varghese, L. ; Pflug, N. ; Thelen, M.

; Makalowski, J. ; Riet, N. ; Göx, H. J. M. ; Rappl, G. ; Altmüller, J. ; Kotrová, M.

; Persigehl, T. ; Hopfinger, G. ; Hansmann, M. L. ; Schlößer, H. ; Stilgenbauer, S. ; Dürig, J. ; Mougiakakos, D. ; von Bergwelt-Baildon, M. ; Roeder, I. ; Hartmann, S. ; Hallek, M. ; Moriggl, R. ; Brüggemann, M. ; Aittokallio, T.

; Iqbal, J. ; Newrzela, S. ; Abken, H. ; Herling, M.

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T-cell prolymphocytic leukemia (T-PLL) is a poor-prognostic neoplasm. Differentiation stage and immune-effector functions of the underlying tumor cell are insufficiently characterized. Constitutive activation of the T-cell leukemia 1A (TCL1A) oncogene distinguishes the (pre) leukemic cell from regular postthymic T cells. We assessed activation-response patterns of the T-PLL lymphocyte and interrogated the modulatory impact by TCL1A. Immunophenotypic and gene expression profiles revealed a unique spectrum of memory-type differentiation of T-PLL with predominant central-memory stages and frequent noncanonical patterns. Virtually all T-PLL expressed a T-cell receptor (TCR) and/or CD28-coreceptor without overrepresentation of specific TCR clonotypes. The highly activated leukemic cells also revealed losses of negative regulatory TCR coreceptors (eg, CTLA4). TCR stimulation of T-PLL cells evoked higher-than normal cell-cycle transition and profiles of cytokine release that resembled those of normal memory T cells. More activated phenotypes and higher TCL1A correlated with inferior clinical outcomes. TCL1A was linked to the marked resistance of T-PLL to activationand FAS-induced cell death. Enforced TCL1A enhanced phospho-activation of TCR kinases, second-messenger generation, and JAK/STAT or NFAT transcriptional responses. This reduced the input thresholds for IL-2 secretion in a sensitizer-like fashion. Mice of TCL1A-initiated protracted T-PLL development resembled such features. When equipped with epitope-defined TCRs or chimeric antigen receptors, these Lckpr-hTCL1AtgT cells gained a leukemogenic growth advantage in scenarios of receptor stimulation. Overall, we propose a model of T-PLL pathogenesis in which TCL1A enhances TCR signals and drives the accumulation of death-resistant memory-type cells that use amplified low-level stimulatory input, and whose loss of negative coregulators additionally maintains their activated state. Treatment rationales are provided by combined interception in TCR and survival signaling.

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