T-Cell Receptor Signaling in Peripheral T-Cell Lymphoma – A Review of Patterns of Alterations in a Central Growth Regulatory Pathway

Abstract

T-cell receptor (TCR) signaling is pivotal in T-cell development and function. In peripheral T-cell lymphomas/leukemias (PTCL/L), histogenesis, transforming events, epidemiology, and clinical presentation are also closely linked to TCR-mediated influences. After reviewing the physiology of normal TCR signaling and cellular responses, we describe here the association of subgroups of PTCL/L with specific patterns of TCR activation as relevant tumor-initiating and/or tumor-sustaining programs. We identify PTCL/L with a functionally intact TCR machinery in which stimulation is possibly incited by exogenous antigens or autoantigens. Distinct from these are tumors with autonomous oncogenic signaling by dysregulated TCR components uncoupled from extrinsic receptor input. A further subset is characterized by transforming events that activate molecules acting as substitutes for TCR signaling, but triggering similar downstream cascades. We finally discuss the consequences of such a functional model for TCR-targeted therapeutic strategies including those that are being tested in the clinic and those that still require further development.

Downmodulation of Tumor Suppressor p53 by T Cell Receptor Signaling Is Critical for Antigen-Specific CD4+ T Cell Responses

“…The ability of TCR signaling to induce Mdm2 and to downmodulate p53 protein expression may also be relevant to the role of p53 as a tumor suppressor. It has been reported that a number of T cell lymphomas show evidence of ongoing TCR signaling pathway activity (Warner et al, 2013), and it is possible that this represents a mechanism for suppressing p53 as one component of growth dysregulation and malignant transformation, a possibility that requires further experimental testing.…”

Targeting Interleukin-2-inducible T-cell Kinase (ITK) and Resting Lymphocyte Kinase (RLK) Using a Novel Covalent Inhibitor PRN694

“…In some settings, it appears that ITK and RLK are redundant signaling molecules because overexpression of RLK in ITK Ϫ/Ϫ mice rescues the Th2 response in a model of asthma (14). Importantly, ITK and RLK are aberrantly overexpressed and activated in T-cell malignancies as well as inflammatory and autoimmune diseases, making these proteins particularly attractive therapeutic targets in these disorders (4,(15)(16)(17).…”

Models for mature T-cell lymphomas—A critical appraisal of experimental systems and their contribution to current T-cell tumorigenic concepts

“…One such candidate might be dysregulated IL-9 [58,59]. Implicated as another central 'co-oncogenic' driver in MTCL pathogenesis is TCR signaling with a differential 'use' of this pathway across MTCL [60]. Constitutive ITK-SYK also represents a model implicating the initiating capacity of aberrant TCR input [61].…”