Retrospective analysis of LAG3, TIGIT, TIM3 and VISTA immune checkpoints expression in hip and knee periprosthetic joint infection

Periprosthetic joint infection (PJI) poses a major clinical challenge, yet underlying mechanisms relating to the local host immune response remain poorly understood and unexplored. Immune checkpoints, known for their role in suppressing T-cell activity and enabling immune evasion in cancer, may similarly contribute to pathogen persistence in PJI. This proof-of-concept study aimed to investigate whether a subset of immune checkpoints is upregulated in PJI. Periprosthetic membrane tissue from patients undergoing hip or knee revision arthroplasty for PJI ( n = 17) or aseptic conditions ( n = 17) was retrospectively collected and stained with immunohistochemical protocols towards immune checkpoints LAG3, TIGIT, TIM3, and VISTA. The percentage of positive cells in ten hotspots was quantified digitally, and immune checkpoint staining was correlated with clinical variables. To substantiate the clinical data, immune checkpoint gene expression was measured locally in a porcine model of implant-associated osteomyelitis at 5–19 days post-infection. The mean percentage of immune checkpoint-positive cells was significantly higher in PJI compared to aseptic failures for LAG3 (2.8% vs. 0.7%), TIGIT (8.1% vs. 5.1%) and VISTA (63% vs. 31%), but not for TIM3. VISTA expression was moderately correlated with a history of PJI and joint type. In pigs, LAG3 and TIGIT transcripts increased progressively at 10–19 days post-infection (4.6-9.9-fold compared to saline-inoculated controls). Upregulation of immune checkpoints in clinical hip and knee PJI indicates localized immune dysregulation. These findings provide a rationale for exploring immune checkpoints as potential biomarkers and non-antimicrobial based future therapeutic targets in PJI.