Identification of biomarkers in cutaneous T cell lymphoma tumors associated with radiotherapy response and durability

Summary: Abstract Body: Radiotherapy (RT) is a common, established treatment for cutaneous T-cell lymphoma (CTCL) but typically only given with palliative intent. Duration of response is often unpredictable and many patients encounter disease progression over time. Identifying biomarkers that may be predictive of tumors that are more likely to progress versus remain in remission is critically important. Herein, we performed spatial transcriptomics and/or multiplex proximity extension immunoassay on punch biopsy and skin tape strip samples, respectively, and 16S rRNA sequencing on lesional swabs on 11 CTCL patients who underwent RT. Patient samples were categorized into progression or remission categories based on clinical follow-up data after ~1 year. Within the post-RT tumor microenvironment (TME) of patients who progressed, we observed an increase in CTCL and tumor-associated markers (JAK3, CCL17, CCL18, CXCL9) and markers related to radiation resistance (SOD2, XBP1, DUX4). Patients who experienced disease remission possessed an increase in Type 1 interferons (IFI6, IFI27, IFI44) and connective tissue markers (COL1A1, FBN1, MMP2, ADAMTS2). Skin tape strip analysis of 368 proteins relevant to inflammation revealed higher levels of VEGFD and IL-13 in cases that progressed. In general, there was a decrease in CTCL-associated biomarkers from pre to post-RT including JAK3, TRBC1, IL32, CD52, and IL2RG in CD3+CD8- T-cells, IL32 and ITK in CD3+CD8+ T-cells, and HMOX1 and TGFB1 in CD68+ macrophages. 16S data showed distinct microbial communities in progression versus remission groups but similar Shannon diversity scores. Staphylococcus capitis was higher in non-lesional samples from remission patients. In summary, RT response is associated with greater durability when there is higher activation of Type 1 interferons, fewer markers of tumor activity and radiation resistance, and a less favorable TME. JoJo Holm¹, Lauren Chrisman¹, Zachary Thomas¹, Spencer Evans¹, Kurt Lu¹, Ziyou Ren¹, Michael Burns², Joan Guitart¹, Alan Zhou¹ 1. Dermatology, Northwestern University Feinberg School of Medicine, Chicago, IL, United States. 2. Biology, Loyola University Chicago, Chicago, IL, United States. Translational Studies: Cell and Molecular Biology