June 2022 - Katharina Rindler

Katharina Rindler, PhD

MedUni Wien RESEARCHER OF THE MONTH June 2022

Primary cutaneous T cell lymphomas comprise a group of hematological malignancies mediated by clonally expanded T cells in the skin. Their most frequent entity, Mycosis fungoides (MF), often remains undiagnosed for years to decades, as its clinical appearance frequently mimics benign inflammatory conditions such as eczema or psoriasis. Although skin lesions often remain stable over many years in most MF patients, in a minority of patients the disease gradually worsens, with spread of malignant cells to blood, lymph nodes and inner organs, a process that is associated with an overall poor prognosis. Factors contributing to this switch from only slowly growing, indolent disease to an aggressive phenotype are only insufficiently understood. We aimed to unravel markers of disease progression by analyzing skin lesions from MF patients of different disease stages using single-cell RNA sequencing. We found a panel of six markers in the malignant clone of MF lesions (i.e. CXCR4, CD69, HSPA1A, ZFP36, TXNIP, and IL7R) to be downregulated with more aggressive clinical behavior. In this study, we also showed that malignant cells were not only present in clinically visible lesions, but that they also populated clinically unaffected, healthy-looking skin in the majority of patients.

Importantly, the abovementioned marker panel showed highest expression levels in malignant cells of clinically normal appearing skin, suggesting some sort of “dormant” state of these cells, and further confirming the association of expression levels with overall disease aggressiveness. In the future this gene panel might not only facilitate the monitoring of disease progression and therapy response but could potentially also be used to modify the biological behavior of MF tumor cells, by preserving an indolent disease stage, or even by reversing the switch from stable to aggressive disease.

Selected Literature

1. Rindler K, Jonak C, Alkon N, Thaler FM, Kurz H, Shaw LE, Stingl G, Weninger W, Halbritter F, Bauer WM, Farlik M, Brunner PM. Single-cell RNA sequencing reveals markers of disease progression in primary cutaneous T-cell lymphoma, Mol Cancer. 2021 Sep 28;20(1):124.
2. Auer K, Bachmayr-Heyda A, Aust S, Grunt TW, Pils D. Comparative transcriptome analysis links distinct peritoneal tumor spread types, miliary and non-miliary, with putative origin, tubes and ovaries, in high grade serous ovarian cancer. Cancer Lett. 2017 Mar 1;388:158-166.
3. Bangert C, Rindler K, Krausgruber T, Alkon N, Thaler FM, Kurz H, Ayub T, Demirtas D, Fortelny N, Vorstandlechner V, Bauer WM, Quint T, Mildner M, Jonak C, Elbe-Bürger A, Griss J, Bock C, Brunner PM. Persistence of mature dendritic cells, TH2A, and Tc2 cells characterize clinically resolved atopic dermatitis under IL-4Rα blockade. Sci Immunol. 2021 Jan 22;6(55):eabe2749.
4. Rindler K, Krausgruber T, Thaler FM, Alkon N, Bangert C, Kurz H, Fortelny N, Rojahn TB, Jonak C, Griss J, Bock C, Brunner PM. Spontaneously Resolved Atopic Dermatitis Shows Melanocyte and Immune Cell Activation Distinct From Healthy Control Skin. Front Immunol. 2021 Feb 24;12:630892.
5. Rindler K, Bauer WM, Jonak C, Wielscher M, Shaw LE, Rojahn TB, Thaler FM, Porkert S, Simonitsch-Klupp I, Weninger W, Mayerhoefer ME, Farlik M, Brunner PM. Single-Cell RNA Sequencing Reveals Tissue Compartment-Specific Plasticity of Mycosis Fungoides Tumor Cells. Front Immunol. 2021 Apr 21;12:666935.