Cutaneous T-cell lymphomas (CTCLs) are a heterogeneous group of blood-related cancers characterized
by chronic inflammation and accumulation of malignant T cells in the skin. Among lymphomas, CTCL is
uniquely characterized by the striking dermal tropism of transformed cells—where exposure to microbes might
contribute to disease etiology. CTCL patients often succumb to bacterial infections, and a correlation between
the presence of certain strains of Staphylococcus aureus and disease severity has been observed.
Commensal and pathogenic bacteria can influence differentiation of naïve T lymphocytes, trigger proliferation
and activation of T cells through production of superantigens (SAgs), and create a permissive
microenvironment for tumor cells by influencing chemokine and cytokine expression. We hypothesize that,
along with genetic predisposition of an individual and mutations acquired by T cells or T lymphocyte
precursors, exposure to S. aureus and SAgs produced by some strains of this pathobiont promotes malignant
transformation and clonal evolution in CTCL.
Prior research by other groups and our preliminary studies implicate S. aureus specifically in CTCL
pathogenesis. We will isolate, sequence and study S. aureus isolates from the skin of CTCL patients (from
tumor sites and unaffected skin) and determine the repertoire of toxins and SAgs produced by these strains.
We anticipate that CTCL-associated isolates will differ in both the ability to produce large numbers of SAg
types per organism and the distribution of their SAg gene content. We will use in vitro methods to evaluate how
SAgs and other toxins and exoproteins produced by skin microbiota of CTCL patients contribute to T cell
activation, proliferation, and malignant transformation.
To further understand the contribution of S. aureus to CTCL pathogenesis and to demonstrate a causal
connection between S. aureus colonization and malignant disease, we will use our new animal model of CTCL
and our germ-free facility to examine the impact of microbial exposure on CTCL initiation and progression. We
will also take advantage of cutting-edge, single-cell, high-throughput technology that enables simultaneous
analysis of surface epitopes, T cell receptor gene rearrangements, and transcriptomics to achieve
unprecedented resolution of the tumor microenvironment in CTCL and to examine changes in the
microenvironment upon S. aureus colonization.
The studies outlined in our proposal will provide significant insight into CTCL pathogenesis and will inform
development of future therapies that are more targeted and less toxic than current chemotherapeutic