Integrated Immune and Molecular Profiling Identifies Prognostic Subgroups and Therapeutic Targets in Chondrosarcoma

Chondrosarcoma (ChS) is a rare bone malignancy with heterogeneous behavior, the molecular and immunological background of which remains unknown. No effective systemic treatment for advanced ChS patients is available. The aim of this study was to develop an immune-mutational classification of ChS and to search for novel prognostic factors and molecular targets. We performed an immunological-molecular profiling of 99 patients diagnosed with primary ChS G1-G3 and dedifferentiated ChS. An expression of 20 immune response markers was assessed by IHC and targeted the next-generation sequencing of 409 genes was performed. Immunological and mutational profiles were correlated with overall survival using a multivariate LASSO-penalized Cox model. Three immunophenotypes were described-"cold" (IMP1), "hot" (IMP2), and "intermediate" (IMP3). IMP1 was the most prevalent in G1 cases, while IMP2 was the most prevalent in dedifferentiated cases. IDH1/2 or TP53 mutations were associated with high-grade ChS (FDR < 0.05). IMP2 was characterized by a higher number of immune infiltrates in the central region of the tumor (HR: 3.3; CI: 1.13-9.8; p < 0.05). IDH1 mutations were present most often in IMP2 cases (HR: 3.8; CI: 1.75-8.1; p < 0.001). Tumor size, dedifferentiated subtype, IDH1 mutation and the presence of IMP2 were identified as independent negative prognostic survival factors in ChS. An immune-mutational classification system for ChS patients was proposed, which may be used to identify those potentially suited for immunotherapy combined with IDH-mutant inhibitors in future research.