Abstract
Cutaneous T-cell lymphoma (CTCL) is a life-debilitating malignancy of lymphocytes homing to the skin. Although CTCL is thought to arise from a combination of genetic, epigenetic, and environmental factors, specific triggers are unclear. The skin is colonized by a unique microbiota and is heavily influenced by its interactions. We hypothesized that adaptive immune responses to skin commensals lead to clonal T-cell proliferation and transformation in the appropriate genetic background. We therefore collected lesional and nonlesional skin microbiota from patients with CTCL to study T cell interactions using skin T cell explants and peripheral, skin-homing CD4+ T cells. By various methods, we identified Bacillus safensis in CTCL lesions, a rare human commensal in healthy skin, and showed that it can induce malignant T cell activation and cytokine secretion. Taken together, our data suggest microbial triggers in the skin microbiota of patients with CTCL as potential instigators of tumorigenesis.
Highlights
Cutaneous T cell lymphoma (CTCL) is a cancer of skin-homing T cells with mycosis fungoides (MF) being the most common subtype
T cell isolates from lesional CTCL skin biopsies showed increased STAT3 phosphorylation compared to non-lesional T cells, which is a characteristic of malignant CTCL T cell populations (Netchiporouk et al, 2014, Sommer et al, 2004). Utilizing these lesional T cell isolates as well as skin-homing peripheral T cells from CTCL patients, we identified B. safensis, but not other patient-isolated skin bacteria, as a potential source of antigenic stimuli driving the clonal proliferation of malignant CTCL T cells
Upon further analysis of these Bacillus species, we identified exclusive 16S rRNA V1V3 amplicon sequence variants in 5 of 7 CTCL patients with >99% identity to a lesional isolate of Bacillus safensis and the representative strain FO-36b (Fig. 3A-C)
Summary
Cutaneous T cell lymphoma (CTCL) is a cancer of skin-homing T cells with mycosis fungoides (MF) being the most common subtype. CTCL is conceptually similar to mucosa-homing lymphocytes in mucosa-associated lymphoid tissue (MALT) lymphoma (Girardi et al, 2004, Isaacson and Du, 2004). Malignant T cells are clonal and proliferate in discrete histological clusters known as Pautrier’s microabscesses within the epidermis (Robson, 2007), presenting as scaly skin patches and plaques (Girardi et al, 2004). With MF often presenting as a fairly indolent, life debilitating disease, diagnosis is challenging and requires tissue sampling, which may not routinely be performed in early stages of disease. Prior studies associated CTCL with HLA class II alleles (Jackow et al, 1996) supporting the already postulated
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