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.

Cutaneous T-cell lymphomas (CTCL) account for approximately 80% of cases of cutaneous lymphomas. Among CTCL, mycosis fungoides (MF) is the most common and most studied type comprising up to 55% of cases. Three different MF stages are recognized in the following order of pathology evolution: patches, plaques and tumor; MF can progress to tumor stage with involvement of other organs, compromising life due to systemic malignant invasion and immunosuppression. Currently, there are not long-lasting treatment for MF. We aimed to understand if angiogenesis, involved in solid tumor progression, could be involved in MF course. For this, we studied both, MF cell lines (HH, Myla) and skin tissues from MF patients at its different stages including healthy skin, according to ethical approval statements. We evaluated the density of blood vessels in skin from MF patients using staining for CD31 by immunohistochemistry. In HH and Myla cell lines, we have studied the presence of angiogenic receptors by western blot and then we have analyzed the effect of 3 angiogenic inhibitors, axitinib, cabozantinib and sunitinib, on cell survival and cell death. We found that there is an increased number of blood vessels in tumor stage compared with patch stage and healthy skin, and in plaque stage compared with patch stage. In HH and Myla cells that express VEGR2 and c-MET, we noticed that although they are sensitive to the angiogenic inhibitors used, axitinib and specially sunitinib reduced significantly cell survival and enhanced cell death at doses between 5-10 micromolar, at 72 hours. We conclude that the density of blood vessels increases with MF progression and thus that angiogenesis takes place during MF pathophysiology. Furthermore, the fact that angiogenic inhibitors already used in tumor treatment provoke MF cell death and affect MF cell survival, suggests that the use of angiogenic inhibitors could be of great interest for controlling MF progression. Future animal model experiments and clinical trials should reveal the potential of angiogenesis inhibition as a new therapeutical option for MF treatment. Citation Format: Natalia Rendon-Serna, Maeva Dufies, Luis Alfonso Correa-Londono, Olga Maria Bermudez-Munoz, Margarita Maria Velasquez-Lopera, Gilles Pages. Angiogenic inhibitors reduce mycosis fungoides cell survival and enhance cell death [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 2650.