A novel prognostic model for osteosarcoma using circulating CXCL10 and FLT3LG

Abstract

Background Osteosarcoma is the most common malignant pediatric bone tumor. Identification of novel biomarkers for early prognostication will facilitate risk-based stratification and therapy. In this study, we investigated the significance of circulating cytokines/chemokines to predict prognosis at initial diagnosis. Experimental design We employed Luminex assays to measure cytokine/chemokine concentrations from blood samples in a discovery cohort of osteosarcoma patients from Texas Children's Hospital (n= 37) and an independent validation cohort obtained from the Children's Oncology Group (n= 233). Following validation of biomarkers, we constructed a multivariable model to stratify patients into risk groups. Results The circulating concentrations of CXCL10, FLT3LG, IFNG, and CCL4 were significantly associated with overall survival in both cohorts. Of these candidates, CXCL10 and FLT3LG were independent from the existing prognostic factor, metastasis at diagnosis, and CCL4 further discriminated cancer-versus-control. By combining CXCL10, FLT3LG and metastatic status at diagnosis, we developed a multivariate model that significantly stratified the patients into four distinct risk groups (p = 1.6e-8). Survival analysis showed that 5-year overall survival rates for the “Low”, “Intermediate”, “High” and “Very-high” risk groups were 77%, 54%, 47%, and 10% respectively, while 5-event-free survival rates were 64%, 47%, 27%, and 0% respectively. Neither CXCL10 nor FLT3LG tumor expression were significantly associated with survival. Conclusions High circulating levels of CXCL10 and FLT3LG predicted worse survival in osteosarcoma. Since both CXCL10 and FL3LG axes are potentially targetable, further study may lead to novel risk-based stratification and therapy in osteosarcoma.

Chemokine profiling in serum from patients with ovarian cancer reveals candidate biomarkers for recurrence and immune infiltration

“…Notably, in the cohort of the present study, there was a negative association between systemic CXCL9 + CXCL10 and RFS (but not OS), which contradicts reports linking intratumoral CXCL9 and CXCL10 with better OS in HGSOC to some extent (13,54). However, the levels of these chemokines were also demonstrated to be associated with worse prognosis in several other cancer types (55)(56)(57)(58)(59)(60). The complexity of surrounding TME can explain the differences in observed outcomes, as the tumor-dependent factors can shift the microenvironment from immune-activating to immune-suppressing.…”

Profiling targetable immune checkpoints in osteosarcoma

“…While we did not quantify IFNγ expression in the available osteosarcoma samples, reports indicate that increased concentrations of circulating IFNγ correlates with inferior outcome in patients with this disease. 50 This supports our finding and the work by Urakawa et al indicating that IDO1 protein expression predicts poor outcome in osteosarcoma. 51 Taken together, these data suggest that the increased IDO1 expression observed in osteosarcoma is a reflection of the inflammatory tumor microenvironment.…”

Development of a novel immune-related genes prognostic signature for osteosarcoma

“…Of note, we identified 10 hub IRGs, namely CXCR3, CXCR4, CCR5, CCL5, CXCL10, CXCL12, CXCL16, OPRL1, S1PR1, and GAL. Among them, CXCR3 28 , CXCR4 29 , CCR5 30 , CCL5 31 , CXCL16 32 , CXCL10 33 , CXCL12 34 and GAL 35 have been widely studied in OS, and are involved in the occurrence, metastasis, and angiogenesis of OS. OPRL1 encodes proteins that are endogenous opioid-related neuropeptides and nociceptin/orphanin receptors, which plays a key role in pain perception and nociception 36 , 37 .…”