Immune checkpoint blockade (ICB) has revolutionised the treatment of metastatic melanoma (MM) which was historically resistant to conventional therapies, yet only a minority of patients experience durable clinical benefit. Dissecting peripheral immune responses to ICB may discern predictive markers of clinical outcome. However, infection with human cytomegalovirus (CMV) can have profound effects on immunity and the extent to which this affects the peripheral immune response to ICB is unclear. Using an agnostic transcriptomic and cytometric assessment of peripheral immune ICB responses across a large cohort of MM patients, I identify dynamic changes in immune composition, activation and adaptive immune cell repertoires. I also determine the contribution of CMV to these changes and describe predictors of clinical outcome.
Firstly, I identify CD8+ T-cells as being the most responsive cell type to ICB treatment and that responses in other peripheral blood mononuclear cell subsets are secondary to CD8+ T-cell ICB response. Next, I find that only B-cell proportion and subset composition are sensitive to ICB treatment. This includes a transient depletion of B-cells and an induction of antibody-secreting cells which associate with clinical outcome. I then characterise these changes and determine that these ICB-mediated effects are largely dependent on CD8+ T-cell activation and production of B-cell chemoattractant CXCL13. Finally, I describe the effects of ICB and CMV on corresponding B-cell receptor and T-cell receptor repertoires. Significantly, I find that B-cells undergo accelerated class switch recombination and somatic hypermutation following ICB, whilst MAIT cells are depleted and associate with clinical outcome. Although CMV infection is a major determinant of MAIT cell changes following ICB, all other identified ICB-mediated effects are independent of CMV serostatus.
In this thesis I present novel findings surrounding B-cell and T-cell responses to ICB treatment and identify predictive markers which may have clinical utility in monitoring patient treatment responses as well as guiding treatment stratification. My observations demonstrate that the response to ICB is multifaceted, involving a coordinated interaction between different cell subsets, driven by CD8+ T-cells. Notably, B-cells cannot be assumed to play a bystander role and my work highlights the importance of B-cell:CD8+ T-cell interactions in the response to ICB and long-term clinical benefit
