The potential role of thioredoxin 1 and CD30 systems as multiple pathway targets and biomarkers in tumor therapy

Abstract

Our progress in understanding pathological disease mechanisms has led to the identification of biomarkers that have had a considerable impact on clinical practice. It is hoped that the move from generalized to stratified approaches, with the grouping of patients into clinical/therapeutic subgroups according to specific biomarkers, will lead to increasingly more effective clinical treatments in the near future. This success depends on the identification of biomarkers that reflect disease evolution and can be used to predict disease state and therapy response, or represent themselves a target for treatment. Biomarkers can be identified by studying relationships between serum, tissue, or tumor microenvironment parameters and clinical or therapeutic parameters at onset and during the progression of the disease, using systems biology. Given that multiple pathways, such as those responsible for redox and immune regulation, are deregulated or altered in tumors, the future of tumor therapy could lie in the simultaneous targeting of these pathways using extracellular and intracellular targets and biomarkers. With this aim in mind, we evaluated the role of thioredoxin 1, a key redox regulator, and CD30, a cell membrane receptor, in immune regulation. Our results lead us to suggest that the combined use of these biomarkers provides more detailed information concerning the multiple pathways affected in disease and hence the possibility of more effective treatment.

Fig. 1

Trx1 has a conserved catalytic site (-Trp-Cys-Gly-Pro-Cys-Lys) that undergoes reversible oxidation to the cysteine-disulfide (Trx-S2) form through the transfer of reducing equivalents to a disulfide substrate (X-S2). In health, the oxidized (1) Trx1 form (Trx-S2) is converted back to the cysteine-thiol reduced (2) form [Trx-(SH)2] by the NADPH-dependent flavoprotein thioredoxin reductase (TrxR), so maintaining balance between oxidized and reduced Trx1 forms, and catalytically interacts with CD30 cell membrane receptor (CD30R) on the immune cells (9). The consequent oxidized (3) and reduced (4) states of CD30R determine its respective ability (5) or inability (6) to engage its ligand CD30L. In this way, it is possible to transduce signals of M and DC intracellular pathways for Treg/Th1/Th17 cytokine production, leading to balance of Th differentiation into Treg/Th1/Th17 cells, for immune response homeostasis

Fig. 2

In tumors, an increase in Trx1 levels (1) leads to abnormal redox cellular regulation determining imbalance between oxidant and antioxidant Trx1(2) and between oxidized and reduced states of RCD30 (3), so establishing RCD30 inability to engage CD30L (4) and transducer signals of intracellular pathways for Treg/Th1/Th17 cytokine production (5). When levels of sCD30 (shed from the plasma membrane upon CD30L binding (6) increase (7), sCD30 binds to CD30L with high affinity blocking CD30/CD30L transmembrane signaling (8). Thus, abnormal increases in the levels of Trx1 and sCD30 (biomarkers 9 of extracellular pathways of Trx1/CD30 target) result in both deregulation of M and DC pathways of Treg/Th1/Th17 cytokine production (biomarkers 5 of intracellular pathways of Trx1/CD30 target) and immunological deficit: Th17 expansion and Treg and Th1-cell functional deficit

Fig. 3

Levels of Trx1/sCD30 and Treg/Th1/Th17 cytokine in serum, tissue, or tumor microenvironment are prognostic and stratification biomarkers for clinical treatment. The CD30/Trx1 system is a potential target in tumor therapy aimed at the simultaneous optimization of the redox and immune system regulation. Normal levels of sCD30 and Trx1 are positive (benefit) biomarkers reflecting the normal functioning of extracellular pathways, while normal levels of Treg/Th1/Th17 cytokines are positive (benefit) biomarkers for the normal functioning of intracellular pathways. Abnormal levels (higher levels of sCD30, Trx1, and Th17 and lower levels of Treg and Th1) are negative (risk) biomarkers for the abnormal functioning of CD30/Trx1 target pathways and so for immunological deficit and a lack of response to therapy