Characterization of High and Low IFNG-Expressing Subgroups in Atopic Dermatitis.

Atopic dermatitis (AD) is one of the most common chronic inflammatory skin diseases, with an increasing number of targeted therapies available. While biologics to treat AD exclusively target the key cytokines of type 2 immunity, Janus kinase inhibitors target a broad variety of cytokines, including IFN-γ. To better stratify patients for optimal treatment outcomes, the identification and characterization of subgroups, especially with regard to their IFNG expression, is of great relevance, as the role of IFNG in AD has not yet been fully clarified. This study aims to define AD subgroups based on their lesional IFNG expression and to characterize them based on their gene expression, T cell secretome and clinical attributes. RNA from the lesional and non-lesional biopsies of 48 AD patients was analyzed by RNA sequencing. Based on IFNG gene expression and the release of IFN-γ by lesional T cells, this cohort was categorized into three IFNG groups (high, medium, and low) using unsupervised clustering. The low IFNG group showed features of extrinsic AD with a higher prevalence of atopic comorbidities and impaired epidermal lipid synthesis. In contrast, patients in the high IFNG group had a higher average age and an activation of additional pro-inflammatory pathways. On the cellular level, higher amounts of M1 macrophages and natural killer cell signaling were detected in the high IFNG group compared to the low IFNG group by a deconvolution algorithm. However, both groups shared a common dupilumab response gene signature, indicating that type 2 immunity is the dominant immune shift in both subgroups. In summary, high and low IFNG subgroups correspond to intrinsic and extrinsic AD classifications and might be considered in the future for evaluating therapeutic efficacy or non-responders.

Whole-Body Imaging for the Primary Staging of Melanomas-A Single-Center Retrospective Study.

BACKGROUND: Melanoma staging at diagnosis predominantly depends on the tumor thickness. Sentinel lymph node biopsy (SLNB) is a common tool for primary staging. However, for tumors of >4 mm with ulceration, 3D whole-body imaging and, in particular, Fluor-18-Deoxyglucose positron emission tomography combined with computed tomography (18F-FDG-PET/CT), is recommended beforehand. This study aimed to investigate the real-world data of whole-body imaging for initial melanoma staging and its impact on the subsequent diagnostic and therapeutic procedures. METHODS: In this retrospective single-center study, 94 patients receiving 18F-FDG-PET/CT and six patients with whole-body computed tomography (CT) scans were included. The clinical characteristics, imaging results, and histologic parameters of the primary tumors and metastases were analyzed. RESULTS: Besides the patients with primary tumors characterized as pT4b (63%), the patients with pT4a tumors and pT3 tumors close to 4 mm in tumor thickness also received initial whole-body imaging. In 42.6% of the patients undergoing 18F-FDG-PET/CT, the imaging results led to a change in the diagnostic or therapeutic procedure following on from this. In 29% of cases, sentinel lymph node biopsy was no longer necessary. The sensitivity and specificity of 18F-FDG-PET/CT were 66.0% and 93.0%, respectively. CONCLUSION: Whole-body imaging as a primary diagnostic tool is highly valuable and influences the subsequent diagnostic and therapeutic procedures in a considerable number of patients with a relatively high tumor thickness. It can help avoid the costs and invasiveness of redundant SLNB and simultaneously hasten the staging of patients at the time of diagnosis.

Image-based response assessment during immunotherapy in skin cancer.

Immune-checkpoint inhibitors and further immunotherapeutic treatment strategies have significantly extended therapy options for melanoma and other skin cancer entities over the last decade. In the context of a broader application of immunotherapeutic approaches, sufficient ways to monitor the course of the disease during therapy are required. Immunotherapies are based on different ways of modulating the immune system. This leads to complex clinical response patterns including pseudoprogression and others, requiring an adaptation of conventional diagnostic imaging tools or the introduction of novel technologies. In this review, current non-invasive imaging approaches for response assessment during immunotherapies in skin cancers as well as their limitations are discussed. To overcome present hurdles, promising alternatives to better address novel imaging features during immunotherapy are depicted giving an outlook on what can be expected in the future.

T-cell functionality testing is highly relevant to developing novel immuno-tracers monitoring T cells in the context of immunotherapies and revealed CD7 as an attractive target.

Cancer immunotherapy has proven high efficacy in treating diverse cancer entities by immune checkpoint modulation and adoptive T-cell transfer. However, patterns of treatment response differ substantially from conventional therapies, and reliable surrogate markers are missing for early detection of responders versus non-responders. Current imaging techniques using 18F-fluorodeoxyglucose-positron-emmission-tomograpy (18F-FDG-PET) cannot discriminate, at early treatment times, between tumor progression and inflammation. Therefore, direct imaging of T cells at the tumor site represents a highly attractive tool to evaluate effective tumor rejection or evasion. Moreover, such markers may be suitable for theranostic imaging. Methods: We mainly investigated the potential of two novel pan T-cell markers, CD2 and CD7, for T-cell tracking by immuno-PET imaging. Respective antibody- and F(ab´)2 fragment-based tracers were produced and characterized, focusing on functional in vitro and in vivo T-cell analyses to exclude any impact of T-cell targeting on cell survival and antitumor efficacy. Results: T cells incubated with anti-CD2 and anti-CD7 F(ab´)2 showed no major modulation of functionality in vitro, and PET imaging provided a distinct and strong signal at the tumor site using the respective zirconium-89-labeled radiotracers. However, while T-cell tracking by anti-CD7 F(ab´)2 had no long-term impact on T-cell functionality in vivo, anti-CD2 F(ab´)2 caused severe T-cell depletion and failure of tumor rejection. Conclusion: This study stresses the importance of extended functional T-cell assays for T-cell tracer development in cancer immunotherapy imaging and proposes CD7 as a highly suitable target for T-cell immuno-PET imaging.