Cell signaling in cutaneous T‐cell lymphoma microenvironment: promising targets for molecular‐specific treatment

Abstract

Cutaneous T-cell lymphomas (CTCL) result from the infiltration and proliferation of a population of T cells in the skin, inducing changes in the activity of both T cells and surrounding skin cells. In the CTCL microenvironment, cell interactions mediated by cell signaling pathways are altered. Defining changes in cell signaling enables to understand Tcell deregulations in the CTCL microenvironment and thus the progression of the disease. Moreover, characterizing signaling networks activated in CTCL stages can lead to consider new molecular biomarkers and therapeutic targets. Focusing on mycosis fungoides (MF), the most frequent variant of CTCL, and S ezary syndrome (SS), its leukemic variant, this review highlights recent molecular and genetic findings revealing modifications of key signaling pathways involved in (1) cell proliferation, cell growth, and cell survival such as MAP kinases and PI3K/Akt; (2) immune responses derived from TCR, TLR, JAK/STAT, and NF-kB; and (3) changes in tissue conditions such as extracellular matrix remodeling, hypoxia, and angiogenesis. Alterations in these signaling networks promote malignant Tcell proliferation and survival, T-cell migration, inflammation, and suppression of immune regulation of malignant T cells, making a skin microenvironment that allows disease progression. Targeting key proteins of these signaling pathways, using molecules already available and used in research, in clinical trials, and with other disease indications, can open the way to different therapeutic options in CTCL treatment.

Proteomic Screening and Verification of Biomarkers in Different Stages of Mycosis Fungoides: A pilot Study

“…The screening of ZAP70 also drew our attention, as it was recently found to be a regulatory point of non-Hodgkin lymphoma that acts via the Ras-Raf-dependent pathway and to induce cell apoptosis ( Bharti et al, 2016 ). In particular, although STAT1, STAT2, STAT3, STAT5, and STAT6 were screened in our study and were already reported to be involved in several MF studies, they did not show significant expression trends among the compared groups but increased significantly in group B, reflecting their involvement in inflammatory diseases ( Bastidas et al, 2018 ; Garcia-Colmenero et al, 2020 ; Gaydosik et al, 2020 ; Rendon-Serna et al, 2021 ).…”

“…We also identified a series of meaningful proteins that have been previously found to be associated with MF. Networks including MAPK, PI3K/Akt, JAK/STAT, NF-κB, TCR, and TLR downstream signalling were activated in malignant T-cells, facilitating ECM remodelling and tumour progression ( Bastidas et al, 2018 ; Seto et al, 2018 ; Kamijo et al, 2018 ; Perez et al, 2020 ; Rendon-Serna et al, 2021 ). The screening of ZAP70 also drew our attention, as it was recently found to be a regulatory point of non-Hodgkin lymphoma that acts via the Ras-Raf-dependent pathway and to induce cell apoptosis ( Bharti et al, 2016 ).…”

Cutaneous Lymphoma and Antibody-Directed Therapies

“…The currently available antibody-directed treatments for cutaneous lymphoma are summarized in Figure 1 . Novel investigative strategies for drug discovery in CTCL will be provided by targeting the key proteins of signaling pathways that stimulate malignant T cells and firing up antitumor immune responses in the CTCL microenvironment [ 49 ].…”

The Role of Tumor Microenvironment in the Pathogenesis of Sézary Syndrome

“…In CTCL skin lesions, there is an increased number of microvessels. Moreover, VEGF is significantly expressed on these cells, and it is produced by neoplastic cells, endothelial cells, histiocytes, fibroblasts, and reactive T-cells [138][139][140].…”

“…Malignant T-cells secrete factors that stimulate the production of MMPs by stroma cells [30]. These two metalloproteinases are upregulated in different types of cancer, and they mediate microvascular proliferation by degrading basement membranes of endothelial cells, facilitating the spread of proliferating vascular cells to the surrounding stroma [138,146,147]. On the other hand, in a rabbit study model, the active form of MMP-5 was reduced in malignant T-cells [148].…”