Dynamic changes in peripheral blood lymphocyte subsets predict the efficacy and prognosis of immune checkpoint inhibitors in metastatic osteosarcoma.
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BACKGROUND: Osteosarcoma (OSA) remains the most common primary malignant bone tumor in children and adolescents, with a poor prognosis for metastatic disease. While immune checkpoint inhibitors (ICIs) have revolutionized cancer treatment, their efficacy in metastatic OSA is limited and highly variable, lacking clear predictive biomarkers. Peripheral blood lymphocyte subsets, reflecting systemic immune status, show promise as non-invasive predictors of ICIs efficacy and patient prognosis, yet their dynamic changes and predictive value in metastatic OSA are largely unexplored. METHODS: This single-center, retrospective study included 14 metastatic OSA patients receiving ICIs. Peripheral blood lymphocyte subsets (CD3+, CD4+, CD8+ T cells, NK cells, and activated T cells like CD4+HLA-DR+, CD8+HLA-DR+) were quantified by flow cytometry at diagnosis, pre-ICIs, and post-ICIs. Overall survival (OS) and treatment response (RECIST 1.1) were evaluated. Statistical analyses, including univariate Cox regression, group comparisons, and Linear Mixed Models (LMM), assessed the relationship between lymphocyte subsets, their dynamic changes, and clinical outcomes. RESULTS: Univariate Cox regression identified pre-ICIs CD8+HLA-DR+ cells, and post-ICIs CD3-CD56+, CD3+CD4+, and CD8+HLA-DR+ cells as protective factors for OS. At diagnosis, CD45+, CD3-CD56+, CD4+HLA-DR+, CD3+CD8+, and CD8+HLA-DR+ cells were significantly higher in patients achieving disease control rate (DCR) versus progressive disease (PD). Post-ICIs, CD3-CD56+, CD3+CD4+, and CD8+HLA-DR+ cells were significantly elevated in the DCR group. LMM revealed dynamic increases in post-ICIs CD3-CD56+ and CD8+HLA-DR+ cells were significantly associated with better treatment response (Time Point × Response P < 0.001 and P = 0.003). Relative increases in post-ICIs CD3-CD56+, CD3+CD4+, and CD8+HLA-DR+ cells were protective for OS. Extrapulmonary metastasis was a significant risk factor for poor OS (HR: 6.75, P = 0.040). CONCLUSION: This study provides the first systematic analysis of dynamic changes in peripheral blood lymphocyte subsets in metastatic OSA patients undergoing ICIs. Our findings suggest that elevated proportions and dynamic increases of peripheral blood CD3-CD56+ (NK cells) and CD8+HLA-DR+ (activated cytotoxic T cells) after ICIs are consistently associated with improved OS and better treatment response. These accessible biomarkers hold potential for predicting ICIs efficacy and guiding individualized treatment strategies in metastatic OSA, warranting further validation in larger, prospective cohorts.