Pretreatment naive T cells are associated with severe irAE following PD-1/CTLA-4 checkpoint blockade for melanoma.

Immune checkpoint inhibitors (ICIs) such as anti-PD-1 and anti-CTLA-4 antibodies are used to induce an immune response against many types of tumors. However, ICIs often also induce autoimmune responses, referred to as immune-related adverse events (irAEs), which occur unpredictably and at varying levels of severity. We utilized high-dimensional immunophenotyping of longitudinal blood samples from patients with metastatic melanoma treated with combination anti-PD-1/CTLA-4 therapy in a clinical trial to characterize alterations in immune profiles induced by combination ICI therapy and to identify immune features associated with severe irAE development. T cell profiling highlighted that ICI therapy induces prominent expansions of activated, CD38hi CD4+ and CD8+ T cells, which are frequently bound by the therapeutic anti-PD-1 antibody, as well as substantial changes in Treg phenotypes. However, neither the baseline frequency nor the extent of expansion of these cell populations was associated with severe irAE development. Rather, naive CD4+ T cell abundance pretreatment was significantly associated with development of severe irAEs and with the number of irAEs developed. These results indicate the abundance of naive CD4+ T cells as a predictive feature for the development of severe irAEs following combination ICI therapy.