Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of chronically inflamed skin lesions containing malignant T cells. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients, the disease never progresses beyond this stage, but in approximately one third of patients, the disease becomes progressive, and the skin lesions start to expand and evolve. Eventually, overt tumors develop and the malignant T cells may disseminate to the blood, lymph nodes, bone marrow, and visceral organs, often with a fatal outcome. The transition from early indolent to progressive and advanced disease is accompanied by a significant shift in the nature of the tumor-associated inflammation. This shift does not appear to be an epiphenomenon but rather a critical step in disease progression. Emerging evidence supports that the malignant T cells take control of the inflammatory environment, suppressing cellular immunity and anti-tumor responses while promoting a chronic inflammatory milieu that fuels their own expansion. Here, we review the inflammatory changes associated with disease progression in CTCL and point to their wider relevance in other cancer contexts. We further define the term “malignant inflammation” as a pro-tumorigenic inflammatory environment orchestrated by the tumor cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL.

Key Points: Staphylococcal enterotoxins activate oncogenic pathways in CTCL. This discovery implies a novel role of microbes as drivers of disease progression.

In patients with cutaneous T-cell lymphoma (CTCL) bacterial infections constitute a major clinical problem caused by compromised skin barrier and a progressive immunodeficiency. Indeed, the majority of patients with advanced disease die from infections with bacteria, e.g., Staphylococcus aureus. Bacterial toxins such as staphylococcal enterotoxins (SE) have long been suspected to be involved in the pathogenesis in CTCL. Here, we review links between bacterial infections and CTCL with focus on earlier studies addressing a direct role of SE on malignant T cells and recent data indicating novel indirect mechanisms involving SE- and cytokine-driven cross-talk between malignant- and non-malignant T cells.

Jak3, STAT3, and STAT5 inhibit expression of miR-22, a novel tumor suppressor microRNA, in cutaneous T-Cell lymphoma

Key Points: Staphylococcal enterotoxins stimulate benign T cells to induce activation of the immunoregulatory Stat3/IL-10 axis in malignant T cells. Colonization with enterotoxin-producing Staphylococcus aureus may promote immune dysregulation in cutaneous T-cell lymphoma.

Key Points: A validated 3-miRNA classifier can effectively predict progression from early- to advanced-stage MF and survival at time of diagnosis. This classifier outperforms existing clinical prognostic factors and paves the way for implementation of personalized treatment in MF.