Alterations in intratumoral and peripheral immune status in recurrent gliomas and their prognostic implications for patients underwent reoperation

Background: Reoperation is a treatment option for recurrent gliomas, yet factors impacting survival following reoperation remain poorly defined. Tumor immunity is profoundly associated with disease progression. Here, we analyze the immune status characteristics and their prognostic implications in recurrent gliomas. Methods: Intratumoral and peripheral immune characteristics between primary and recurrent gliomas were compared by conducting immunohistological staining and hematological examination with our in-house samples, and analyzing bulk and single-cell sequencing data from publicly available sources. Survival analysis was conducted to identify immunological markers with prognostic significances. Results: We observed a significant reduction in peripheral lymphocyte count, while an elevation in neutrophil-tolymphocyte ratio (NLR) and red cell distribution width-to-platelet ratio (RPR) in patients with recurrent gliomas than in newly-diagnosed patients. Higher NLR and RPR indicated worse survival following reoperation in recurrent patients. Transcriptomic and immunohistological analysis showed an increased infiltration of tumor- associated macrophages (TAMs) and CD8+ + T cell in recurrent gliomas compared to primary gliomas in both IDH-wildtype and mutant subtypes. Moreover, the abundance of TAMs emerged as an independent indicator for an inferior prognosis in recurrent gliomas. Single-cell profiling revealed a significant heterogeneity in the phenotypes of TAMs between primary and recurrent gliomas. Notably, TAMs enriched in recurrent gliomas exhibited elevated expression of interferon-gamma-induced genes, multiple immunosuppressive molecules (TGFB1, CD276), and increased activity in glycose and lipid metabolism, indicating metabolic reprogramming. Conclusion: Recurrent gliomas demonstrate augmented immune cell infiltration, but they fail to overcome TAMsinduced immunosuppression. Immunosuppressive indices, including TAM abundance, peripheral NLR and RPR, have prognostic implications for recurrent gliomas.