Staphylococcus aureus alpha-toxin inhibits CD8⁺ T cell-mediated killing of cancer cells in cutaneous T-cell lymphoma

ABSTRACT

Staphylococcus aureus and its toxins have been linked to disease progression and mortality in advanced stages of cutaneous T-cell lymphoma (CTCL). CD8⁺ T cells play a crucial role in anti-cancer responses and high CD8⁺ T cell numbers in tumor lesions are associated with a favorable prognosis in CTCL. Here, we show that CD8⁺ T cells from both healthy donors and Sézary syndrome patients are highly susceptible to cell death induced by Staphylococcal alpha-toxin, whereas malignant T cells are not. Importantly, alpha-toxin almost completely blocks cytotoxic killing of CTCL tumor cells by peptide-specific CD8⁺ T cells, leading to their escape from induced cell death and continued proliferation. These findings suggest that alpha-toxin may favor the persistence of malignant CTCL cells in vivo by inhibiting CD8⁺ T cell cytotoxicity. Thus, we propose a novel mechanism by which colonization with Staphylococcus aureus may contribute to cancer immune evasion and disease progression in CTCL.

KEYWORDS:

• Alpha-toxin
• Staphylococcus aureus
• CTCL
• CD8⁺ T cells
• cytotoxicity

Acknowledgments

The authors would like to acknowledge the patients that donated blood for this study as well as the photophoresis team at Copenhagen University Hospital Bispebjerg for providing the patient samples.

Authors’ contributions

E.B. performed experiments; E.B., T.B.B. analysed the data and made the figures; E.B., S.M.A, C.N., A.W-O., M.G., S.F., T.H., B.G.J.S., L.M.L., H.F., S.B.K., L.M.R.G., R.C., L.I., T.K., C.M.B., C.G., J.C.B., A.W., M.H.A, T.B.B., and N.Ø. designed the research. E.B., T.B.B. and N.Ø. wrote the original draft of the paper. E.B., S.M.A, C.N., A.W-O., M.G., S.F., T.H., B.G.J.S., L.M.L., H.F., S.B.K., L.M.R.G., R.C., L.I., T.K., C.M.B., C.G., J.C.B., A.W., M.H.A, T.B.B., and N.Ø. reviewed and edited the manuscript. T.B.B., M.H.A. and N.Ø. supervised the project. N.Ø. acquired the funding.

Disclosure of Potential Conflicts of Interest

Jürgen C. Becker declares the association with the pharma firm Takeda as an external advisor. Niels Ødum has an advisory consultant honorarium from Micreos human Health B.V. All other authors declare no potential conflicts of interest.

Supplementary material

Supplemental data for this article can be accessed on the publisher’s website.

Additional information

Funding

This work was supported by the Novo Nordisk Research Foundation [NNF14OC0012345]; LEO Foundation [NA]; Danish Research Council (Danmarks Frie Forskning Fond) [NA]; Danish Cancer Society (Kraeftens Bekaempelse) [NA]; Lundbeck Foundation [NA]; LINAK A/S Nordborg [NA]; Aage Bangs Foundation [NA]; Kraeftfonden [NA]; Fight Cancer Program (Knaek Cancer) [NA].