Background

Mycosis fungoides (MF) and Sézary syndrome (SS) are the most frequent epidermotropic cutaneous T-cell lymphomas (CTCL), both originating from CD4+ lymphocytes. There is no curative treatment for these orphan diseases, healing is rare and 25% may progress to higher stage disease. Although the malignant and reactive lymphocytes were studied extensively, little is known about the role of the dermal-epidermal microenvironment in MF and SS. The group of Hodak et al proposed an important role of dermal fibroblasts, but our knowledge on other dermal components is poor.

Methods

Publicly available data of single cell RNA sequencing from 5 CTCL patient biopsies, 4 inflammatory dermatoses and 13 healthy donors were re-analyzed by focussing on the non-lymphocytic microenvironment. The data was compared to healthy skin and other benign inflammatory disorders that underwent the same laboratory techniques, similarly from the freely accessible GEO database. Statistical analysis was carried out using SeqGeq. Selected results were confirmed at protein level.

Results

Although using different sequencing and in silico techniques, the data structure was comparable permitting a comparison among studies. The cellular composition of CTCL biopsies importantly differed from healthy skin, and inflammatory dermatoses, even after exclusion of lymphocytes. In particular, lower numbers of fibroblasts, keratinocyte hyperproliferation and a macrophagic infiltrate were prominent. Subpopulations of these were also studied. When focussing on the non-cellular microenvironment, a higher production of S100A8 and S100A9 and for example CXCL9 and CXCL10 were observed from various cell populations.

Conclusion

In conclusion the cellular composition of skin in advanced CTCL is importantly disturbed, also when ignoring the lymphocytic compartment. Besides the reactive lymphocytic infiltrate macrophages seem to play an important role in the microenvironment. Fibroblasts seem to be key players in orchestrating cell-cell interactions, although being importantly reduced in their number. Endothelial cells seem to be rather passive.



Figure 1 displaying the distribution of cell subpopulations in the cutaneous tumor microenvironnement. 1/A: cell subpopulations displayed on UMAP-graph. 1/B: mean relative proportions of cell subpopulations in healthy skin, inflammatory dermatoses and CTCL. 1/C: colour codes.