(P 139) IMMUNOGENOMIC PROFILING OF CHONDROSARCOMA REVEALS DISTINCT IMMUNE PHENOTYPES AND PROGNOSTIC MUTATIONS

Objective: Chondrosarcomas (ChS) are considered “cold” tumors due to poor immunotherapy responses, and their immune and molecular characteristics remain poorly understood given the lack of effective therapies. We aimed to identify distinct immune phenotypes and key genetic alterations correlating with grade, outcomes, and potential therapeutic targets.

Methods: Ninety-nine ChS patients underwent immune (tumor microarray immunohistochemistry with 20 immune-cell and checkpoint markers) and genomic profiling (targeted sequencing of 409 genes for somatic mutations and tumor mutational burden). Unsupervised clustering and multivariate Cox analysis were used to define immune phenotypes and prognostic factors.

Results: Clustering of immune markers revealed three phenotypes (“cold”, “hot”, “intermediate”) that differed by histologic grade (p < 0.001), with high-grade tumors shifting from “cold” to predominantly “hot” profiles. Molecular analysis showed low TMB (~2 mutations/Mb) and frequent mutations in IDH1/2 (~40%) and TP53 (~15%), enriched in high-grade tumors, and ARID1A (~12%) mutations predominantly in grade 2–3. High-grade tumors had greater genomic complexity. Despite increased immune infiltration, the hot phenotype was associated with worse survival; in multivariate analysis, hot (and intermediate) tumors had ~3-fold risk of death, with IDH1 mutation conferring a similar hazard. High intratumoral CD3+ T-cell density and PD-L1 expression were also linked to worse prognosis.

Conclusion: High-grade ChS harbor more mutations and immune infiltrates yet confer poorer survival, implying an immunosuppressive microenvironment. IDH1/2 mutations and a “hot” immune phenotype define a subset with poor prognosis. This supports exploration of combined IDH-targeted therapy with immune checkpoint blockade to improve outcomes.