Spatially Guided and Single Cell Tools to Map the Microenvironment in Cutaneous T-Cell Lymphoma

Abstract

Mycosis fungoides (MF) and Sézary syndrome (SS) are two closely related clinical variants of cutaneous T-cell lymphomas (CTCL). Previously demonstrated large patient-to-patient and intra-patient disease heterogeneity underpins the importance of personalized medicine in CTCL. Advanced stages of CTCL are characterized by dismal prognosis, and the early identification of patients who will progress remains a clinical unmet need. While the exact molecular events underlying disease progression are poorly resolved, the tumor microenvironment (TME) has emerged as an important driver. In particular, the Th1-to-Th2 shift in the immune response is now commonly identified across advanced-stage CTCL patients. Herein, we summarize the role of the TME in CTCL evolution and the latest studies in deciphering inter- and intra-patient heterogeneity. We introduce spatially resolved omics as a promising technology to advance immune-oncology efforts in CTCL. We propose the combined implementation of spatially guided and single-cell omics technologies in paired skin and blood samples. Such an approach will mediate in-depth profiling of phenotypic and molecular changes in reactive immune subpopulations and malignant T cells preceding the Th1-to-Th2 shift and reveal mechanisms underlying disease progression from skin-limited to systemic disease that collectively will lead to the discovery of novel biomarkers to improve patient prognostication and the design of personalized treatment strategies.

The Role of Cytokines in Cutaneous T Cell Lymphoma: A Focus on the State of the Art and Possible Therapeutic Targets

“…However, the mechanisms involved in the progression from early indolent stages to aggressive ones are still far from being understood. Several players are involved and connected, such as gene alterations, cytokines, and microenvironment cells [11,12,72,78,[283][284][285][286][287][288][289].…”

Spatial cell graph analysis reveals skin tissue organization characteristic for cutaneous T cell lymphoma

“…While several studies have explored the spatial heterogeneity of tumor microenvironment in CTCL and its potential relevance in prognosis 10,11 , a systematic quantification of spatial tissue heterogeneity in the context of CTCL does not exist. This prompted us to generate imaging-based spatially resolved protein abundance maps of skin tissue samples from CTCL, AD, and PSO patients treated at the University Hospital Erlangen, using multi-epitope ligand cartography (MELC) 12,13 .…”