The Microenvironment’s Role in Mycosis Fungoides and Sézary Syndrome: From Progression to Therapeutic Implications

Abstract

Background: Mycosis fungoides (MF) and Sezary Syndrome (SS) are the most common cutaneous T-cell lymphomas. It has been hypothesized that the interaction between the immune system, cutaneous cells, and neoplastic elements may play a role in MF/SS pathogenesis and progression. Methods: This paper aims to revise in a narrative way our current knowledge of the microenvironment’s role in MF/SS. Results and Conclusions: Literature data support a possible implication of microenvironment cells in MF/SS pathogenesis and progression, opening up new therapeutic avenues.

The Role of Tumor Microenvironment in the Pathogenesis of Sézary Syndrome

“…Few studies addressing the presence of Bregs in CTCL are available. Interestingly, decreased Bregs are observed in CTCL progression, and it is hypothesized that Bregs suppress the activity of tumor cells in the blood [14,53]. Other B-cells are also decreased in CTCL, such as CD19+ CD24hiCD27+ Bcells, CD19+ CD38hi B-cells, together with IL-10-producing B-cells in CTCL progression [53].…”

“…The NKG2D is the main activating receptor of the NK cells, and it binds to major histocompatibility complex (MHC) class I homologs (MICA and MICB) and UL-16 binding proteins (ULPB)-1 to 5, that function as signals of cellular stress [57,58]. Upon binding to NKG2D ligand (NKG2DL) expressed in malignant cells, the NK cells attack by degranulation of perforin and granzyme and production of IFN-γ and TNF-α [14]. In a process called trogocytosis, the cell-to-cell contact allows the migration of the NKG2DL of the tumor cell to the NK cell.…”

“…Dendritic cells (DCs) are professional antigen-presenting cells. They prompt immune responses by activating naïve T-cells at a mature state and promote tolerance by deleting self-reactive thymocytes, mediating the anergy of mature T-cells, and generating Tregs at an immature state [14]. The Th2 cytokines secreted in the SS tumor microenvironment suppress the maturation of DCs.…”

“…The IL-4 and IL-13 Th2 cytokines induce the production of CCL18 by M2 macrophages. The CCL18 binds to CCR8, a receptor expressed by Th2, Treg cells, and eosinophils (Figure 5) [14,82,83]. TAMs producing CCL18 are observed in CTCL patients, and serum levels of CCL18 are associated with a poorer prognosis [64,84].…”

“…Biologic response modifiers (ECP, interferon-α, and retinoids) show prolonged responses, suggesting an essential role of immunomodulation in controlling neoplastic proliferation. Increasing evidence shows the influence of the tumor microenvironment characterized by reactive cells, chemokines, and cytokines in the clinical behavior of SS, and these interactions gradually drive an antitumor response towards a tolerogenic milieu [13,14]. Understanding the tumor microenvironment is essential to the development of new therapies to improve survival and, maybe, reach a curative treatment for this aggressive and morbid disease.…”