Keratinocytes present Staphylococcus aureus enterotoxins and promote malignant and non-malignant T cell proliferation in cutaneous T cell lymphoma.

in The Journal of investigative dermatology by Ziao Zeng, Chella Krishna Vadivel, Maria Gluud, Martin R J Namini, Lang Yan, Sana Ahmad, Morten Bagge Hansen, Jonathan Coquet, Tomas Mustelin, Sergei B Koralov, Charlotte Menne Bonefeld, Anders Woetmann, Carsten Geisler, Emmanuella Guenova, Maria R Kamstrup, Thomas Litman, Lise-Mette R Gjerdrum, Terkild B Buus, Niels Ødum

TLDR

  • The study investigates how a type of bacteria called Staphylococcus aureus (S. aureus) affects the growth of cancer cells called T-cells in the skin. The study found that the bacteria and a protein called Staphylococcal enterotoxin (SE) can make the cancer cells grow more quickly and release a chemical called IL-2. The study also found that the bacteria and SE can make the cancer cells grow more quickly and release IL-2 even when the cancer cells are not in contact with the bacteria. The study suggests that the bacteria and SE play a key role in the growth of the cancer cells in the skin.

Abstract

Cutaneous T-cell lymphoma (CTCL) is characterized by malignant T-cells proliferating in a unique tumor microenvironment (TME) dominated by keratinocytes. Skin colonization and infection by Staphylococcus aureus (S. aureus) is a common cause of morbidity and suspected of fueling disease activity. Here we show that expression of HLA-DR, high-affinity receptors for Staphylococcal enterotoxins (SE), by keratinocytes correlates with IFN-γ expression in the TME. Importantly, IFN-γ induces HLA-DR, SE-binding, and SE-presentation by keratinocytes to malignant T-cells from Sézary syndrome (SS) patients, and malignant and non-malignant T-cell lines derived from SS and Mycosis fungoides patients. Likewise, preincubation of keratinocytes with supernatant from patient-derived SE-producing S. aureus triggers proliferation in malignant T-cells and cytokine release (including IL-2), when cultured with non-malignant T-cells. This is inhibited by pre-treatment with engineered bacteriophage S. aureus-specific endolysins. Furthermore, mutations in the HLA-DR binding sites of SE type-A, and siRNA-mediated knockdown of Janus Kinase-3 (JAK3) and IL-2Rγ block induction of malignant T-cell proliferation. In conclusion, we show that, upon exposure to patient-derived S. aureus and SE, keratinocytes stimulate IL-2Rγ/JAK3-dependent proliferation of malignant and non-malignant T-cells in an environment with non-malignant T-cells. These findings suggest that keratinocytes in the TME play a key role in S. aureus mediated disease activity in CTCL.

Overview

  • The study investigates the role of Staphylococcus aureus (S. aureus) in cutaneous T-cell lymphoma (CTCL) and how it affects the tumor microenvironment (TME).
  • The study focuses on the expression of HLA-DR, high-affinity receptors for Staphylococcal enterotoxins (SE), by keratinocytes in the TME and its correlation with IFN-γ expression in the TME. The study also investigates the induction of malignant T-cell proliferation by S. aureus and SE in an environment with non-malignant T-cells. The study aims to answer the question of whether keratinocytes in the TME play a key role in S. aureus mediated disease activity in CTCL.

Comparative Analysis & Findings

  • The study compares the outcomes observed under different experimental conditions, including the expression of HLA-DR, SE-binding, and SE-presentation by keratinocytes to malignant T-cells from Sézary syndrome (SS) patients, and malignant and non-malignant T-cell lines derived from SS and Mycosis fungoides patients. The study also compares the proliferation and cytokine release of malignant and non-malignant T-cells in an environment with non-malignant T-cells upon exposure to patient-derived S. aureus and SE. The study identifies significant differences in the results between these conditions, including the induction of malignant T-cell proliferation by S. aureus and SE in an environment with non-malignant T-cells, which is inhibited by pre-treatment with engineered bacteriophage S. aureus-specific endolysins. The study also identifies key findings that support the hypothesis that keratinocytes in the TME play a key role in S. aureus mediated disease activity in CTCL.

Implications and Future Directions

  • The study's findings have significant implications for the field of research and clinical practice, as they suggest that keratinocytes in the TME play a key role in S. aureus mediated disease activity in CTCL. The study identifies limitations, such as the need to investigate the role of other TME cells and the need to investigate the effects of S. aureus and SE on other types of CTCL. The study suggests possible future research directions, such as investigating the role of other TME cells in S. aureus mediated disease activity in CTCL and investigating the effects of S. aureus and SE on other types of CTCL.
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