Malignant inflammation in cutaneous T-cell lymphoma

– A hostile takeover

Cutaneous T-cell lymphomas (CTCL) are characterized by the presence of skin lesions containing malignant T cells in the background of a chronic inflammatory cell infiltrate. Early disease presents as limited skin patches or plaques and exhibits an indolent behavior. For many patients the disease never progresses but in approximately one third of patients the disease becomes progressive and the skin lesions start to expand and evolve.

Progressive MF
Progressive MF. a–c Example of a patient with progressive MF that during a 3-year period (2002–2004) presents with increasing skin involvement and inflammation. The patient progressed from a clinical stage IA disease with limited patches and plaques to b, c clinical stage IB disease with patches and plaques involving more than 10 % of the skin surface area

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.

Progressive MF
MFlesionsdisplay different levels of inflammation. a–c Illustrative skin lesions from a patient with MF displaying varying degrees of inflammation

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 malignant T cells and discuss some of the mechanisms driving the development of malignant inflammation in CTCL.

Progressive MF
A model of malignant inflammation. a–c Schematic illustration of progression from a early indolent CTCL with few malignant T cells b, c to more advanced disease increasingly dominated by Th2-biased inflammation and malignant T cells. d In early indolent disease, the expansion of the malignant T cells is kept in check by a cellular anti- tumor immune response involving CD8+ T cells, Th1 cells, and NK cells. e In time, malignant T cell endogenous (e.g., genetic and epigenetic alterations) and exogenous (e.g., irradiation, toxins, microbes, chemicals, drugs) events can enable the malignant T cells to take control of the tumor microenvironment, thereby inhibiting the cellular anti-tumor immune response while stimulating the accumulation and/or activation of certain types of benign immune cells and stromal cells (f) that produce pro-tumorigenic factors which directly or indirectly foster the survival and expansion of the malignant T cells

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Malignant inflammation in cutaneous T-cell lymphoma
- A hostile takeover

Thorbjørn Krejsgaard1, Lise M. Lindahl2, Nigel P. Mongan3, Mariusz A. Wasik4, Ivan V. Litvinov5, Lars Iversen2, Erik Langhoff6, Anders Woetmann1, Niels Odum1

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Malignant T Cells Secrete Galectins and Induce Epidermal Hyperproliferation and Disorganized Stratification in a Skin Model of Cutaneous T-Cell Lymphoma

Christenze Thode1, Anders Woetmann2, Hans H. Wandall3, Michael C. Carlsson3, Klaus Qvortrup4, Claudia S. Kauczok5, Marion Wobser5, Andreas Printzlau6, Niels Ødum2 and Sally Dabelsteen1

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Acknowledgements

This work was supported by research funding from the Danish Research Council, the Novo Nordic Foundation, the Novo Nordic Foundation Tandem program, the Lundbeck Foundation, the Danish Cancer Society (Kræftens Bekæmpelse), and the Danish Cancer Society and TV2 "Knæk-Cancer-Program", strategic grant from the Faculty of Health Sciences, University of Copenhagen, and "Læge Sophus Carl Emil Friis og hustru Olga Doris Friis Legat".