Cancer Immunol Res. 2026 Jul 31. doi: 10.1158/2326-6066.CIR-25-1639. Online ahead of print.
ABSTRACT
Immune checkpoint inhibitor (ICI) therapy is often associated with immune-related adverse events including inflammatory arthritis (ICI-IA). However, the mechanisms underlying ICI-IA, especially its recurrence, are not well understood. In this study, we sought to elucidate mechanisms of recurrent ICI-IA by analyzing longitudinal synovial fluid (SF) samples from patients with ICI-IA. SF samples were collected from six ICI-IA patients at the first and second occurrences of ICI-IA and analyzed with single-cell RNA sequencing (n=3), single-cell TCR sequencing (n=3), single-cell BCR sequencing (n=3), and flow cytometry (n=6). SF samples from cancer-naïve osteoarthritis patients (n=6) were used as negative controls. Analysis revealed that effector CD8+ T cells and PD-1hiCXCL13hiCD4+ T cells were enriched in the SF of ICI-IA patients. Ninety three percent and fifty percent of the top ten expanded clones of effector CD8+ T cells and PD-1hiCXCL13hiCD4+ T cells, respectively, were shared between the first and second ICI-IA flare. These top clones were characterized by the production of pro-inflammatory type 1 cytokines including IFN, TNF, and IL-21, especially in the second flare, suggesting immune memory responses to cognate antigen. Cell-cell communication analysis suggested that effector CD8+ T cells and PD-1hiCXCL13h CD4+ T cells interacted with each other and with myeloid cells and B cells through chemokines (CXCL9/10/11/13, CCL3) and cytokines (MIF, IL-2/7/15/21). Overall, longitudinal SF analysis from ICI-IA patients revealed the expansion of effector CD8+ T cells and PD-1hiCXCL13hiCD4+ T cells with type 1 cytokine signatures that potentially contribute to development or recurrence of ICI-IA.
PMID:42536056 | DOI:10.1158/2326-6066.CIR-25-1639