The Role of the Innate Immune System in the Treatment Response of Advanced Melanoma Patients Treated with Immunotherapy

Immunotherapy is a type of cancer treatment that augments the patient’s immune system to eradicate tumour cells. In melanoma, immunotherapy, specifically anti-PD-1 and anti-CTLA-4 immune checkpoint inhibitors (ICI), has revolutionised the treatment of advanced-stage melanoma as evidenced by the five-year survival drastically improving from 6%, prior to ICI, to 52%. A significant issue facing these patients is that the majority will either not respond to therapy or develop resistance. Understanding the complex and dynamic mechanisms that underpin tumour eradication by immunotherapy activated immune cells will enable the discovery of future drug targets to improve patient response and survival to immunotherapy. The essential role of innate immune cells in immunotherapy response is largely unknown. This thesis explores how Natural Killer (NK) cells and macrophages influence immunotherapy response in advanced-stage melanoma patients, using multiplex immunohistochemistry (mIHC), RNA sequencing analysis, single-cell RNA sequencing analysis, flow cytometry, mass-cytometry and co-culture models. This thesis identifies activated and differentiated NK cells as important contributors to the response of melanoma patients treated with immunotherapy. More importantly, NK cells may play an important role in patients with MHC class I loss. Additionally, this thesis investigates the phenotype and function of macrophages in melanoma patients treated with immunotherapy. Through comprehensive phenotypic analysis, we discovered that CD16+ C1q+ macrophages contribute to mediating immunotherapy response via potentially recruiting CD8+ cytotoxic T cells to the tumour microenvironment. Together, these important studies highlight the contributions of the innate immune system in augmenting the effectiveness of ICI