Issue in the Tissue: Immune Landscapes in Melanoma and Inborn Errors of Immunity

Abstract

This thesis, "Issue in the Tissue: Immune Landscapes in Melanoma and Inborn Errors of Immunity", investigates the immune landscapes in two distinct contexts: melanoma and primary immune regulatory disorders (PIRDs). It emphasizes how local tissue immunity influences disease progression, therapy response, and patient prognosis. Leveraging cutting-edge multiplex imaging technologies, such as imaging mass cytometry, the research provides deep spatial insights into immune cell compositions and their interactions within diseased tissues. The first part of the thesis focuses on advanced-stage melanoma. Immunotherapy with immune checkpoint inhibitors (ICI), particularly anti-PD-1 therapy, has revolutionized melanoma treatment, yet a significant proportion of patients fail to respond. Through spatial profiling, the research reveals that responders exhibit an influx of cytotoxic T-cells and circulating myeloid-derived macrophages (MDMs) into the tumor microenvironment (TME). In contrast, non-responders demonstrate the dominance of suppressive macrophages and a lack of effective T-cell infiltration. Furthermore, solitary progressors—patients who experience isolated tumor progression despite overall treatment response—show a distinct immune profile characterized by elevated CD39+ T-cells and impaired tissue residency markers (CD69, CD103). These findings suggest that not only the presence but also the localization and differentiation state of immune cells critically determine therapeutic success. The second part of the thesis examines immune dysregulation in patients with PIRDs, particularly those presenting with enteropathy. Diseases such as activated PI3K delta syndrome (APDS), STAT1 gain-of-function (STAT1-GOF), and STAT3-related disorders (STAT3-HIES and STAT3-GOF) were studied. Blood immunophenotyping revealed that PIRD subgroups could be differentiated based on distinct T-cell maturation and activation profiles. Tissue analyses indicated that PIRD-associated gut inflammation features a unique immune environment compared to classical inflammatory bowel disease (IBD), with reduced T-cell and B-cell infiltration and diminished activation states. These findings highlight the necessity for tailored therapeutic approaches in managing PIRD-related enteropathy, distinct from standard IBD treatment regimens. Across both parts, the thesis underscores the critical role of spatial immune profiling in understanding disease mechanisms and improving therapeutic strategies. It advocates that considering tissue-resident immune features and cell-cell interactions—rather than solely peripheral blood biomarkers—is essential for advancing personalized medicine in oncology and immunology.