Thesis defense Mick van Eijs

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This thesis explores the systemic and local immunological mechanisms of immune-related adverse events (irAEs) associated with immune checkpoint inhibitor (ICI) therapy by investigating blood and tissue immune responses in patients with irAEs and evaluating the effects of immunosuppressants on tumor immunity and irAE-related inflammation. The first part (Chapters 2–5) focuses on the mechanisms behind irAEs. Chapter 2 provides an overview of the clinical aspects of irAEs, including their incidence, ICI-type-specific disease patterns, basic treatment concepts, and underlying genetic and immunological mechanisms. We advocate for prospective studies into the long-term sequelae of ICI therapy and validation cohorts with sufficient power to differentiate irAE mechanisms from the effects of ICI class, tumor type, and antitumor response. Chapter 3 examines peripheral blood immune responses in irAEs. No peripheral blood predictors for irAEs were found before ICI initiation. IrAEs following anti-PD-1 monotherapy showed a Th1-dominant response, but no cellular changes compared to patients who did not develop irAEs. However, irAEs following combined anti-CTLA-4 and anti-PD-1 therapy were linked to an early increase in effector memory CD4+ T cell proliferation and broader immune activation. Chapter 4 characterizes the immune cell infiltrate in ICI colitis and ulcerative colitis. We found a relative increase in CD8+ T cells in colitis after anti-PD-1-based treatment, with activated, cycling CD8+ tissue-resident memory (TRM) cells identified as cytotoxic drivers of both ICI colitis and ulcerative colitis and inflammation spatially focused at the epithelial-lamina propria interface. In Chapter 5, we use single-cell RNA sequencing to study intraepithelial and lamina propria T cells in ICI colitis. We found that compartmental organization of T cell subsets was partly lost in ICI colitis, with T cells increasing especially in the epithelium. Cytotoxic CD4+ T cells infiltrated the epithelium specifically in colitis after combined anti-CTLA-4 plus anti-PD-1 therapy, but not after anti-PD-(L)1 monotherapy. The second part (Chapters 6–8) focuses on the management of irAEs. Chapter 6 reviews evidence from mouse and clinical studies regarding the effects of various immunosuppressants, including corticosteroids and TNF inhibition, on cancer control and survival following ICI therapy. Recommendations are provided for preclinical studies, clinical research, and patient care to optimize irAE treatment while maintaining ICI efficacy. Chapter 7 investigates blood and tissue from patients with irAEs who responded to corticosteroids alone or required second-line immunosuppression. We found that steroid-unresponsive irAEs were associated with a stronger Th1/Th17 response. T cell activation and proliferation persisted in steroid non-responders, while tissue lymphocytes rapidly decreased in patients with ICI colitis who responded to steroids. Chapter 8 presents a case series of five patients who developed hematologic malignancies following anti-PD-1-based ICI therapy for solid tumors. Possible links between ICI therapy and the development of hematologic malignancies are discussed. Finally, Chapter 9 summarizes the key findings of this thesis in the context of recent literature and proposes directions for future research.