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Immune checkpoint inhibitor (ICI) therapy has dramatically changed the field of oncology. In patients with eligible cancer types that are ICI-responsive, the response is often durable and may even lead to cure of metastatic disease. However, the success of ICI therapy comes with a “darker side” in terms of immune-related adverse events (irAEs).

The aim of this thesis is twofold: understanding the mechanisms behind irAEs and exploring the immunological effects of immunosuppressives administered for irAEs. A variety of multi-omics techniques was used to study tissue and blood immune responses in the context of irAEs in ICI-treated patients, including (spectral) flow cytometry, (single-cell) RNA-sequencing and multiplex proteomic assays, such as imaging mass cytometry. We found that irAEs following different ICI therapies show distinct immune responses. For instance, anti-PD-1 treatment results in a Th1-dominant response, while combined anti-CTLA-4 and anti-PD-1 therapy leads to more widespread immune activation, as well as proliferation and cytotoxic transformation of CD4+ T cells. Additionally, we gained spatial insight in the pathophysiology of ICI-associated colitis and found that inflammation is focused at the lamina propria-epithelial interface. We also reviewed the effect of various immunosuppressive drugs administered for irAEs on antitumor immunity and explored biomarkers that may predict whether patients with irAEs will respond to steroids. In conclusion, this thesis sheds light on the immune mechanisms behind irAEs and proposes ways to improve patient care through more personalized treatment strategies. Together, these findings aid in designing treatment algorithms to optimally treat irAEs, without compromising the effectiveness of ICI therapy.