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

Simple Summary While most patients with cutaneous T-cell lymphoma (CTCL) may be diagnosed with early-stage disease, approximately 25-30% of those patients will unexpectedly progress to the advanced stage with an unforeseeable course of progression and response to treatment. Therefore, it is of pivotal importance to decipher the exact biological events governing disease aggressiveness to identify early those patients who will progress, and to design personalized treatment strategies for them. We propose that the way forward should entail a combination of advanced spatially resolving and tissue disruptive single-cell transcriptomics tools to enable deep phenotypic and molecular profiling of the benign immune and malignant T-cell populations in the two different disease compartments and thus acquire a global view of the inter-patient and intra-tumor heterogeneity. This will promote the development of novel molecular biomarkers for improved prognostication and personalized treatment to improve the survival outcomes and quality of life of chronic cancer patients with MF and SS. Mycosis fungoides (MF) and Sezary 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.