Reciprocal interaction of cutaneous T-cell lymphoma cells, the reactive infiltrate, and the lesional microbiome

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Mycosis fungoides (MF), the most common form of cutaneous T-cell lymphoma (CTCL), is characterized by the proliferation of malignant T cells in a chronic inflammatory environment. Although MF often shows an indolent disease course, a subset of patients exhibits an aggressive course with early tumor development, systemic involvement, and high disease-specific mortality. Currently, it is not known what distinguishes indolent from aggressive MF forms. Given the genetic homogeneity of the disease, extrinsic factors are discussed, e.g., the composition of the cutaneous microbiome. Indeed, we have recently shown that a shift in the cutaneous microbiome is associated with the promotion of epithelial cancers. Notably, bacteria frequently colonize MF lesions and, because of the compromised skin barrier, dysbiosis occurs. Patients with advanced disease frequently die of sepsis rather than of direct organ involvement by the malignancy. On the other hand, clinical observations suggest that bacteria, particularly Staphylococcus aureus (S. aureus), play a direct role in MF progression, e.g. by contributing to a tumor-promoting microenvironment. Our previous studies indicated that bacterial superantigen (SA)-mediated interactions of CTCL cells with the reactive inflammatory infiltrate play a role. Furthermore, we observed that the presence of S. aureus is correlated with the abundance of SA-reactive T-cell receptor (TCR) Vβ families, a finding suggesting that the reactive infiltrate is stimulated by SA, regardless of antigen specificity. The results of preliminary single-cell transcriptomic studies are in line with such tumor-promoting interactions of reactive and malignant T cells. Unfortunately, small patient cohorts – typical in rare diseases – are a challenge for statistical analysis of microbiome data. Thus, the conventional computational methods and models must be accompanied by advanced specialized techniques in order to draw reliable conclusions. Our working hypothesis suggests that there is a reciprocal interaction between the composition and the dynamics of the lesional microbiome and the course of CTCL because of its effect on the tumor microenvironment, particularly the reactive T-cell infiltrate. Thus, we will scrutinize the reciprocal action of malignant cells, the reactive infiltrate, and the microbiome. Specifically, we will determine the correlation of comprehensive single-cell transcriptomic and TCR repertoire analyses of MF lesions composing the malignant CTCL clone, the reactive T-cell infiltrate, and additional stromal cells, with the lesional microbiome. We will validate our observations in a larger series of biobanked formalin-fixed paraffin-embedded clinically annotated, sequential CTCL tissue samples. In selected cases we will use spatially resolved transcriptomics. The expected results will allow discovery of prognostic markers for aggressive disease and developing adequate therapeutic strategies.