Adejoorin, I. | bioRxiv Science

bioRxiv2025

Single Cell Analysis of pBMCs of Psoriasis patients reveals distinct CD4+ T cell phenotypes associated with response to IL-23 blockade.

The use of IL-23 inhibitors (IL-23i) for psoriatic diseases has resulted in significant improvement in disease symptoms for many patients. The extent of disease improvement following IL-23 blockade varies across patients with psoriasis; however, the immunologic factors associated with a good or poor response to IL-23 blockade remain unclear. Here, we utilized peripheral blood mononuclear cells (pBMCs) collected through the MINIMA clinical trial (NCT04271540) and applied single-cell RNA sequencing to profile circulating immune populations from 27 patients with psoriasis or psoriatic arthritis, aiming to identify cellular features associated with a response to IL-23 blockade. We identified populations of CD4+ T cells whose abundance in circulation before treatment was associated with improved skin disease following IL-23i treatment. Circulating CD4+ T cells that demonstrate transcriptomic features of Th1-like cells were associated with better psoriasis skin improvement and had transcriptomic signatures resembling T cells identified in psoriasis lesional skin. Further, decrease in levels of IL-17A and IFN{gamma} in serum each correlated with improvement in PASI levels. These results suggest that immune cell features detectable in blood may be informative in identifying patients with psoriasis who are likely to have a robust clinical response to IL-23 blockade.

immunology↗

bioRxiv2025

Pre-treatment naive T cells are associated with severe irAE following PD-1/CTLA4 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 in ICI-treated patients. The immunologic factors that predispose patients to the development of severe irAE are largely unclear. Here, we utilized high dimensional mass cytometry immunophenotyping of longitudinal blood samples from patients with metastatic melanoma treated with combination anti-PD-1/CTLA4 ICI therapy in the context of a clinical trial to characterize alterations in immune profiles induced by combination ICI therapy and to identify immune features associated with development of severe irAEs. Deep 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 regulatory T cell phenotypes. However, neither the baseline frequency nor the extent of expansion of these cell populations was associated with development of severe irAEs. Rather, single cell-association testing revealed naive CD4+ T cell abundance pre-treatment as significantly associated with the development of severe irAEs. Biaxial gating of naive CD4+ T cells confirmed a significant positive association of naive CD4+ T cell proportion and development of a severe irAE and with the number of irAEs developed in this cohort. Results from this broad profiling study indicate the abundance of naive CD4+ T cells as a predictive feature for the development of severe irAEs following combination anti-PD-1/CTLA4 ICI therapy.

immunology↗